Role of mTOR in physiology and pathology of the nervous system
Lukasz Swiech1, Malgorzata Perycz1, Anna Malik1, Jacek Jaworski⁎
Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology in Warsaw, 4 Ks. Trojdena St., 02-109 Warsaw, Poland
Received 14 July 2007; received in revised form 9 August 2007; accepted 10 August 2007
Available online 24 August 2007
Mammalian target of rapamycin (mTOR) is a serine–threonine protein kinase that regulates several intracellular processes in response to
extracellular signals, nutrient availability, energy status of the cell and stress. mTOR regulates survival, differentiation and development of
neurons. Axon growth and navigation, dendritic arborization, as well as synaptogenesis, depend on proper mTOR activity. In adult brain mTOR is
crucial for synaptic plasticity, learning and memory formation, and brain control of food uptake. Recent studies reveal that mTOR activity is
modified in various pathologic states of the nervous system, including brain tumors, tuberous sclerosis, cortical displasia and neurodegenerative
disorders such as Alzheimer's, Parkinson's and Huntington's diseases. This review presents current knowledge about the role of mTOR in the
physiology and pathology of the nervous system, with special focus on molecular targets acting downstream of mTOR that potentially contribute
to neuronal development, plasticity and neuropathology.
© 2007 Elsevier B.V. All rights reserved.
Keywords: mTOR; Nervous system; Rapamycin; Neuronal development; Synaptic plasticity; Neurodegenerative disorders
A serine–threonine protein kinase called mammalian target
of rapamycin (mTOR) is mostly known for its role in cell
proliferation and growth in non-neural cells. The major role of
this kinase is to merge extracellular instructions with informa-
tion about cellular metabolic resources and to control the rate of
anabolic and catabolic processes accordingly. In terms of mo-
lecular mechanism, mTOR is thought to act primarily by phos-
phorylating eIF-4E binding protein (4E-BP) and p70 ribosomal
S6 protein kinase (p70S6K), which are important regulators of
protein translation . However, “chemical genomics” per-
formed on yeast identified 400 mutants whose phenotypes
(measured as rates of survival) were changed in the presence of
rapamycin, a specific inhibitor of mTOR [2,3]. A large number
of genes whose expression is down- or upregulated by mTOR
inhibition were also identified by gene expression profiling of
Drosophila melanogaster cells treated with rapamycin .
Analysis of these rapamycin-dependent mutants suggested that
brane trafficking, microtubule and actin cytoskeleton dynamics.
Although neurons are post-mitotic (non-proliferative), the
size of the neuronal cell soma is also controlled by mTOR .
Indeed, one of the characteristic features of diseases accompa-
nied by increased mTOR activity is tissue hypertrophy, which
also affects the nervous system, where neuronal cells are en-
larged and cell morphology is highly disturbed (see below).
However, recent studies revealed a much broader involvement
of mTOR in neuronal development, showing that axon gui-
dance, dendrite development, dendritic spine morphogenesis,
all require its activity [6–9]. But a role for mTOR in neuronal
physiology extends beyond the developmental period, since
mTOR activity is essential for several forms of synaptic plas-
ticity that underlie processes of learning and memory formation
Available online at www.sciencedirect.com
Biochimica et Biophysica Acta 1784 (2008) 116–132
Abbreviations: Aβ, β-amyloid; AD, Alzheimer's disease; BDNF, brain-
derived neurotrophic factor; HD, Huntington's disease; CD, cortical displasia;
4E-BP1, eIF-4E binding protein; KO, knockout; NF1, type I neurofibromatosis;
p70S6K, p70 ribosomal S6 kinase; PD, Parkinson's disease; PI3K, phosphoi-
nositide-3′ kinase; PRAS40, proline-rich AKT substrate 40 kDa; Raptor,
regulatory-associated protein of mTOR; Rheb, Ras homolog enriched in brain;
Rictor, rapamycin-insensitive companion of mTOR; RNAi, RNA interference;
SIN1, mammalian stress-activated protein kinase interacting protein 1; mTOR,
mammalian target of rapamycin; TSC, tuberous sclerosis; TSC1, tuberous
sclerosis complex protein 1, hamartin; TSC2, tuberous sclerosis complex protein
2, tuberin; TSC1/2, tuberous sclerosis complex
⁎Corresponding author. Tel.: +48 22 597 07 55; fax: +48 22 597 07 15.
E-mail address: firstname.lastname@example.org (J. Jaworski).
1These authors equally contributed to this work.
1570-9639/$ - see front matter © 2007 Elsevier B.V. All rights reserved.
[10–14]. Recently, mTOR was also shown to regulate other
brain functions, for example a control of food uptake .
Due to the key role that mTOR plays in neuronal physiology,
it is not surprising that mTOR signaling is disturbed under
various neuropathological conditions. Changed mTOR activity
has been reported in brain tumors, tuberous sclerosis, cortical
displasia and neurodegenerative disorders such as Alzheimer's,
Parkinson's and Huntington's disease [16–22].
Yet, in cases of either physiological processes or neuropa-
thology, our knowledge about molecular events downstream of
mTOR is rather rudimentary. In this review we discuss current
advances in our understanding of mTOR function and dys-
function in the nervous system, at the same time searching for
proteins whose expressions are mTOR-dependent and im-
portant for normal neuronal physiology.
2. mTOR—an important convergence point in cell signaling
mTOR kinase activity is modulated in response to various
stimuli such as trophic factors, mitogens, hormones, amino
acids, cell energy status and cellular stress, including ischemia,
heat shock, DNA damage and viral infections [23–27]. These
positive and negative signals converge on mTOR, the resultant
processes in the cell. mTOR kinase activity regulates numerous
cellular processes both in positive (for example, protein trans-
lation) and negative (for example, autophagy) ways. Therefore
the searches for downstream targets of this kinase have greatly
intensified recently [3,4,28,29]. A very important tool for these
studies is the specific inhibitor of mTOR—rapamycin. Rapa-
mycin in the complex with FK506-binding protein (FKBP12)
binds the N-terminal domain of mTOR and thus inhibits its
enzymatic activity. Most data concerning cellular activities of
mTOR are based on the use of rapamycin. Only recently has
RNA interference (RNAi) technology extended the panel of
tools to study mTOR cellular functions and signaling pathways
involving mTOR [7,30–32].
2.1. mTORC1 and mTORC2 protein complexes
In mammalian cells, mTOR forms two heteromeric and
functionally distinct protein complexes called mTORC1 and
is involved in the control of a wide variety of cellular processes
such as transcription, translation, autophagy, cell cycle and
microtubule dynamics (Fig. 1) (for a review on mTOR
functions, see [34,35]). On the other hand, rapamycin-
insensitive mTORC2 regulates actin cytoskeleton dynamics
and controls the activity of two protein kinases—Akt and
PKCα (Fig. 1) [32,36]. Prolonged rapamycin application causes
sequestration of mTOR by FKBP12–rapamycin–TORC1
inactive complex and indirectly leads to mTORC2 inhibition
. Apart from mTOR only a GβL protein (mLST8/GβL) is
shared by TORC1 and 2 complexes [32,38,39]. Other mTOR
partners differ between TORC complexes. Raptor (regulatory-
associated protein of mTOR) and PRAS40 (proline-rich AKT
substrate 40 kDa) are incorporated into mTORC1 [30,31,40]
while Rictor (rapamycin-insensitive companion of mTOR),
SAPK-interacting protein (SIN) and Protor were found in
mTORC2 (Fig. 1) [32,41,42].
The role of individual proteins constituting mTORC com-
plexes has not yet been definitely established. mTOR has been
shown to possess catalytic activity and can phosphorylate
several target proteins, including p70 ribosomal S6 protein
kinase (p70S6K), eIF-4E binding protein (4E-BP1) and Akt
[1,24,34,36,38]. However, its catalytical activity requires the
be crucial for phosphorylation of Akt on serine 473 [41,43].
mLST8/GβL most likely has a structural function and facilitates
mTORC1 interactions with its protein targets such as p70S6K
mTORC1 activity, since mLST8 knockout (KO) animals die
Fig. 1. Schematic diagram of mTOR activity control. Stimulation of several
receptors at the plasma membrane by mitogens, trophic factors and neu-
rotransmitters leads to mTOR activation via Ras and class I PI3K- and ERK-
dependent pathways. An increased level of amino acids (AA) induces mTOR
mTOR activating TSC2. mTOR bound to Raptor protein forms the TORC1
complex that is responsible for the control of protein translation, transcription,
autophagy and microtubule dynamics. mTOR forms also TORC2 complex with
Rictor, which regulates actin dynamics and phosphorylate Akt and PKC. Ric—
Rictor; Rap—Raptor; arrows and oval arrows—activation and inhibition of
target protein or cellular process, respectively.
117L. Swiech et al. / Biochimica et Biophysica Acta 1784 (2008) 116–132
much later than Raptor KOs . A positive effect of mLST8
was also shown to be exerted on mTORC2-controlled actin
display similar developmental defects and die at midgestation
(embryonic day 10.5) [44,45]. These phenotypic similarities
indicate that mLST8 is indispensable for mTORC2 function.
The function of Raptor and Rictor is to enhance substrate
specificity of mTOR towards mTORC1 and mTORC2 targets,
respectively [31,36]. Recently a new, important partner of
mTOR, PRAS40 protein, has been described . PRAS40
binds to mTORC1 and inhibits its activity . PRAS40
dissociationfromthecomplex iscritical formTORC1activation
and is regulated via direct phosphorylation of PRAS40 by Akt
of the mTORC2 complex, but its function has not yet been
elucidated . There are two major questions open at the
moment concerning the activities of mTOR complexes. Do
mTORC1 and mTORC2 have common mechanisms for their
activity control, and do these two complexes influence each
2.2. Activation of mTOR pathway
A canonical pathway for mTOR activation starts with
activation of receptor tyrosine kinases by mitogens, trophic
factors (like brain-derived neurotrophic factor—BDNF) or
hormones (insulin) (Fig. 1). This, in turn, leads to the activation
of phosphoinositide-3′ kinase (PI3K) viarecruitment of the SH2
domain containing adaptor proteins and Ras, and increased
production of phosphatidylinositol 3,4,5-trisphosphate (PIP3)
(Fig. 1). The immediate consequence of increased PIP3 levels is
recruitment of 3-phosphoinositide-dependent protein kinase 1
(PDK1) and Akt to the cell membrane and subsequent
phosphorylation of Akt by PDK1 and mTORC2, a recently
can phosphorylate tuberin (TSC2) [47–49] which, together with
hamartin (TSC1), constitutes a tuberous sclerosis complex,
TSC1/2, a GTPase-activating protein (GAP) for Rheb (Ras
homolog enriched in brain protein) (Fig. 1) [50–52]. Inactiva-
tion of TSC2, caused by Akt-mediated phosphorylation, results
in increased Rheb-GTP levels in the cell that has a stimulatory
effect on mTOR activity (Fig. 1) [50–52]. Surprisingly, recent
studies show that Rheb-GTP can activate mTORC1, but not
mammalian human embryonic kidney cells (HEK) . By
contrast, Rheb-GTP appears to inhibit the mTORC2 activity
However, the picture of mTOR activity regulation emerging
from recent studies is much more complex than that of the
canonical pathway. Akt is not the only inhibitor of TSC2. And
activation of extracellular signal-regulated kinases (ERKs), as
well as of p90 ribosomal S6 kinase 1 (RSK), leads to the
phosphorylation and subsequent inhibition of tuberin (Fig. 1)
[54,55]. On the other hand, Akt can induce mTORC1 activity
bypassing TSC1/2, directly phosphorylating PRAS40 .
Additionally, translationally controlled tumor protein (TCTP),
recently identified as a guanine exchange factor for Rheb in
Drosophila, activates mTOR without TSC1/2 engagement
(Fig. 1) .
While phosphorylation of tuberin by Akt and ERKs leads to
inhibition of TSC1/2 activity, and to the activation of mTOR,
phosphorylation of tuberin driven by AMP-dependent protein
kinase (AMPK) has an opposite effect . AMPK is activated
by high cellular levels of adenosine monophosphate, which
indicates energy deficits, and AMPK-driven mTOR down-
regulation serves as a turn-off switch of the cellular anabolic
program. Recently Inoki and collaborators , studying the
Wnt signaling pathway, revealed that full inhibition of mTOR
requires coincident TSC2 phosphorylation by AMPK and
glycogen synthase kinase 3 beta (GSK3β) (Fig. 1).
One more, evolutionary conserved, pathway of mTOR ac-
tivity control is dependent on the level of amino acids available
to the cell. In contrast to hormones, growth factors and mitogens
that engage class I PI3K for mTOR activation, amino acids
recruit class III PI3K–Vps34 for this purpose (Fig. 1) [59–61].
Interestingly,this pathway leads at the same time to a mTORC1-
dependent increase of controlled protein expression, and a re-
duction of autophagocytosis .
Trophic factors,hormones and amino acids were allshown to
regulate activity of mTOR in neurons. In addition, neuron-
specific substances such as neurotransmitters can induce mTOR
activity. In particular activation of NMDA-type ionotropic and
metabotropic receptors for glutamate, the major excitatory neu-
rotransmitter in the brain, has been extensively studied in this
2.3. Cellular effectors of mTOR activation
Although interest in mTOR has dramatically increased,
relatively little is known about the number and identity of
mTOR activity effectors, especially in vertebrates. Traditional
research approaches based on the investigation of single
protein–protein interactions or individual gene expression
have allowed for identification of very few potential mTOR
activity effectors. The best known are proteins important for
regulation of translation, such as p70S6K and 4E-BP1 .
There is also evidence linking mTOR to protein phosphatase
PP2A , cytoplasmic linker protein CLIP-170 , eEF2
kinase (eEF2K) , nucleophosmin , glycogen synthase
[68,69] and hypoxia inducible factor 1-α  and a few others
discussed below (see also Table 1). However currently, thanks
to the development of novel approaches for studying mTOR-
dependent genes and proteins, based on functional genomics
and proteomics, performed in yeast, Drosophila and mammals,
this list is rapidly expanding.
The most extensive large-scale screens on the role of mTOR
selecting agent to screen libraries of yeast mutants lacking or
overexpressing individual genes for proteins that can regulate or
are regulated by TOR kinase [3,28]. Over four hundred proteins
participating in transcription, translation, protein stability, inter-
cellular transport, cell cycle, mitochondrial metabolism and
microtubule dynamics have been identified. In addition to the
yeast studies, gene expression profiling of Drosophila S2 cells
118L. Swiech et al. / Biochimica et Biophysica Acta 1784 (2008) 116–132
mTOR-related proteins and neuronal development
Protein namemTOR dependenceNeuronal effect
Axon and dendrite development
4E-BP1R—phosphorylation inhibition Ox—simplification of dendritic
arbor (hippocampal neurons) 
KnD—simplification of dendritic
arbor (optic tectal neurons) 
GluR2TSC2−/− —increase in mRNA
levels. TSC patients' giant cells —
decrease in mRNA levels 
R—increased transcription ASH2-like proteinOx—axon guidance phenotype
(neuromascular junction model) 
KnD—simplification of dendritic
arbor (cerebellar neurons) 
dependent protein kinase II
dependent protein kinase II
R—inhibition of local translation 
TSC2−/−—decreased mRNA levels Ox—increased arborization of
dendritic tree (hippocampal neurons) 
KnD—simplification of dendritic arbor 
chemorepellent slit induces cofilin translation
(retinal neurons) 
KnD—decrease in NGF induced neurite outgrowth
PIn—simplification of dendritic arbor
(hippocampal neurons) 
PA—increase in dendritic arbor complexity
(cerebellar neurons) 
PIn—inhibition of neuronal
activity—induced dendritic arbor growth
(optic tectal neurons) 
KnD—simplification of dendritic arbor
(hippocampal neurons) 
Ox—promotes axon formation
(hippocampal neurons) [172,173]
KnD—shortening of axons
(hippocampal cells) ;
inhibition of NGF-induced neurite outgrowth (PC12) 
KnD—decreased dendrite length
(hippocampal neurons) 
Ox—additional neurites outgrowth
(ganglion neurons) 
KnD—inhibition of neurites outgrowth
(ganglion neurons) 
KnD—prevents Aβ-induced inhibition of neurite outgrowth
(cortical neurons) 
KnD—simplification of dendritic arbor
(hippocampal neurons) 
R—inhibition of local translation 
GABA(A) receptor subunitsTSC2−/−—increase in mRNA
levels. TSC patient giant cells —
decrease in most subunit mRNA levels 
GRIN-A/NR1R—inhibition of BDNF-induced
association with polysomes in dendrites 
interacting protein 1 (GRIP1)
LIM domain kinase 1 (LIMK1)
R—inhibition of BDNF-induced
association with polysomes in dendrites 
R—inhibition of BDNF-induced
association with polysomes in dendrites 
Microtubule-associated protein 2
R—inhibition of local translation 
R—inhibition of BDNF-induced association with
polysomes in dendrites 
Neuronal pentraxin 1TSC2−/−—decreased mRNA levels 
p70S6KR—phosphorylation inhibition 
Postsynaptic density protein 95
R—inhibition of insulin induced local translation  Ox—simplification of dendritic arbor
(hippocampal neurons) 
KnD—increased number of dendrites 
Ox—inhibition of NGF induced neurite
outgrowth (PC12) 
KnD—inhibition of NGF-induced neurite outgrowth
(PC12 and DRG neurons) 
Ox—acceleration of neurite outgrowth induced by HB-GAM
(N18 neuroblastoma cells) 
KnD—reduced length of neurites in presence of NGF
Rabex-5R—increased growth of KO yeast strain 
Sphk1/Sphingosine kinase 1R—decreased growth of KO yeast strain 
Syndecan 3R—inhibition of BDNF-induced association
with polysomes in dendrites 
R—increased growth of KO yeast strain Ubiquitin-conjugating
enzyme E2 B (Ube2B)
Dendritic spines development
GluR2 TSC2−/−—increase in mRNA levels.
TSC patients giant cells—
decrease in mRNA levels 
R—increased transcription 
Ox—increase in spine density and size
(hippocampal neurons) 
KnD—inhibition of spine morphogenesis 
(neuromuscular junction model) 
Ox—increase in synapse number
(hippocampal neurons) 
protein kinase II beta
TSC2−/−—decreased mRNA levels 
(continued on next page)
119L. Swiech et al. / Biochimica et Biophysica Acta 1784 (2008) 116–132
grown in presence of rapamycin has been performed . Rapa-
mycin turned out to modulate expression of 90 genes, in vast
majority belonging to the group of proteins engaged in the
control of various aspects of transcription and translation .
Finally, the analysis of gene transcription levels in cells lacking
the TSC2 gene, and derived from the nervous system, revealed
changes in expression of several genes involved in neuronal
2.4. Major cellular processes controlled by mTOR activation
As mentioned above, mTORC complexes, once activated,
control a myriad of cellular processes, a detailed description of
which is beyond the scope of this review. In this section we
focus on mTOR involvement in the regulation of the processes
contributing to the nervous system physiology and pathology,
including control of protein translation, with special focus on
local protein synthesis in dendrites and axons of neurons,
autophagy and microtubule dynamics.
Most of the mature eukaryotic mRNAs possess a 7-methyl-
guanine cap structure and a poly-A tail at their 5′- and 3′-
termini, respectively, which cooperate in control of initiation of
translation .During translation initiation, the cap structure is
recognized by the eIF4F initiation complex that includes eIF4E
protein . However, under basal conditions, this protein
remains bound to 4E-BP1, which prevents formation of eIF4F
. Several translation-inducing signals lead to mTOR-
mediated phosphorylation of 4E-BP1, which causes eIF4E
release, allowing for the formation of the functional eiF4F
complex and initiation of translation [72,73]. Also recruitment
of another initiation factor, eIF4B, to the initiation complex is
mTOR-dependent [74,75]. But the eIF4B needs to be
phosphorylated by the p70S6K to associate with the translation
initiation complex [74,75]. However, p70S6K is much better
known for its kinase activity towards S6 protein. Through this
phosphorylation, p70S6K is believed to increase the rate of
production of proteins involved in regulation of the processes of
translation (for example, ribosomal proteins and translation
elongation factors), encoded by mRNAs containing a 5′-oligo-
pirymidine tract (5′ TOP), and therefore also increase
translational capacity of the cell . Nevertheless, cultured
hepatocytes derived from mice lacking p70S6K1 and 2 exhibit
normal regulation of 5′TOP mRNA translation . This new
experimental evidence challenges the current view on the
importance of the p70S6K-S6 pathway in control of rapamycin-
dependent 5′TOP mRNA translation [72,78]. In addition to
control of translation initiation, mTOR kinase is also involved
in regulation of the translation at the stage of elongation. It was
demonstrated that phosphorylation of translation inhibitor–
elongation factor 2 kinase (eEF2K) by p70S6K is sensitive to
rapamycin . eEF2K phosphorylation inhibits the eEF2
kinase activity towards eEF2 . Dephosphorylated eEF2 be-
comes active and so the translation elongation rate increases
The presence of polysomes, Golgi apparatus and mRNA has
been reported in the proximity of synapses and in the growth
cones of axons of neuronal cells, strongly suggesting that
protein translation in neurons might occur locally in discrete
locations and is independent of general translation regulation in
the cell . Several lines of evidence suggest that mTOR
kinase is one of the crucial regulators of this phenomenon. For
example, BDNF induces rapamycin-sensitive induction of
translation in dendrites of cortical neurons cultured in vitro
. Furthermore, BDNF presence in the culture medium
induces phosphorylation of tuberin and subsequent activation of
mTOR, followed by phosphorylation of p70S6K and 4E-BP1
and induction of translation in synaptosomal fractions (bio-
chemical fraction of neuronal cells containing synaptic proteins)
. Greenberg's group demonstrated that indeed, up to 80
mRNA species associate with polysomes in synaptodendritic
fraction in a rapamycin-dependent fashion upon BDNF
stimulation of neurons in culture . Several of these
mRNAs were encoding proteins crucial for synaptic plasticity,
such as CamKIIα, subunits of NMDA and AMPA type
ionotropic glutamate receptors, Homer 2 and LIMK1. This
helps to understand the role which mTOR plays in the long-term
Table 1 (continued)
Protein name mTOR dependenceNeuronal effect
Dendritic spines development
KnD—decease in synapse number 
R—inhibition of local translation  KnD—inhibition of LTD induced spine retraction
(hippocampal neurons) 
KnD—overexpression of liprin1α disturbing
GRIP1–LAR interaction decreases spine number
(hippocampal neurons) 
KnD—increased spine volume (cortical neurons) 
protein 1 (GRIP1)
R—inhibition of BDNF-induced
association with polysomes in dendrites 
LIM domain kinase 1 (LIMK1)R—inhibition of BDNF-induced
association with polysomes in dendrites 
R—inhibition of insulin induced local
R—increased Snk plasmid copy
number in yeast strain 
R—increased transcription 
Postsynaptic density protein 95
Serum-inducible kinase (Snk)
KnD—dendritic spine density decrease (striatal neurons in vivo) 
Ox—loss of mature spines (hippocampal neurons) 
SP1-like proteinOx—synaptogenesis phenotype
(neuromascular junction model) 
R—rapamycin treatment; KnD—knockdown bysiRNA, knockoutandoverexpression of kinasedead or dominantnegative mutantwereconsidered; Ox—overexpression
of wild-type or constitutively active forms were taken into account; PIn—pharmacological inhibition; PA—pharmacological activation; HB-GAM—heparin-binding
growth-associated molecule; DRG—dorsal root ganglion; NGF—nerve growth factor.
120L. Swiech et al. / Biochimica et Biophysica Acta 1784 (2008) 116–132
synaptic changes underlying learning and memory. Finally,
Inamura et al.  demonstrated that BDNF induces an mTOR-
dependent dephosphorylation of eEF2 and an increase in
translation elongation rate in dendrites of cortical neurons
cultured in vitro.
In addition to protein synthesis, the rate of protein
degradation depends on mTOR activity. Autophagy is an
evolutionary conserved process of catabolic cell response to
poor nutrient conditions that employs the lysosomal pathway
(for a review, see [62,83]). Activation of mTOR by trophic
factors (TSC–Rheb pathway) or by increased amino acid
availability (class III PI3K–Rheb pathway), results in the
inhibition of autophagy [62,84]. By contrast, inhibition of
mTOR by decreased amino acid availability, energetic stress
resulting in AMPK activation, or rapamycin can lead to
increased autophagy [62,84]. Unfortunately, downstream
effectors of mTOR involved in the control of autophagy are
not known. It is worth noting that several autophage-inducing
drugs (including rapamycin) are considered to be potential
therapeutic agents for several diseases, including neurodegen-
erative disorders .
Apart from the regulation of protein anabolism and cata-
bolism, mTOR directly interacts with CLIP-170/Restin protein
in several organisms and increases binding of CLIP-170 to the
microtubules (MTs) and therefore influences microtubule
dynamics [65,85]. CLIP-170/Restin was the first described
member of the microtubule plus-end-tracking group of proteins
(+TIPs) known to bind only dynamic plus-ends of microtubules
. Binding of CLIP-170 to microtubules increases net
microtubule growth by promoting “rescue” phases over catas-
trophes during the microtubule cycle . CLIP-170 was also
shown to link endocytic vesicles to microtubules in in vitro
assays, suggesting its potential role in intracellular transport
. CLIP-170 and its mTOR dependence have not yet been
studied in the context of brain physiology or pathology, but
several other +TIPs have been shown to be crucial for various
aspects of neuronal physiology.
3. mTORkinase activityin physiology of the nervous system
Availability of selective inhibitors of mTOR, methodological
advances in genetic modification of neuronal cells, and an
increase in interest in mTOR functions have greatly accelerated
our understanding role of mTOR in the physiology of the
nervous system. Although research has primarily focused on the
mTOR-dependent translation impact on synaptic and brain
plasticity [10,13,89], several recent studies addressed questions
about mTOR involvement in neuronal development  and
aspects of brain physiology other than plasticity . Below we
discuss these recent findings, focusing on the proteins known to
contribute to the neuronal physiology, and whose production
and/or activity is potentially regulated by mTOR. It is important
to note, however, that only in a few cases was a direct link
between individual protein, mTOR and particular processes in
neurons established. In most cases the potential link is only a
suggestion based on bioinformatics of recent large-scale screens
for mTOR targets (see above), and the available knowledge of
molecular mechanisms underlying neuronal development and
3.1. mTOR impact on neuronal development
Neuronal development is a process divided into several
sequential and partially overlapping stages during which the
for particular neuronal classes, is acquired. During this process,
initial synaptic connections are established and synaptic activity
fine tunes formation of the neuronal network .
One of the early steps in neuronal development is dif-
ferentiation and directional growth of axons towards their
targets. Navigation of the axonal growth cone is regulated by
gradients of several chemoattractants (for example netrin-1) and
chemorepellents (Semaphorin3A, Slit), which together prevent
aberrant formation of neuronal networks. Growing axons
contain translational machinery at the growth cones, and direc-
tional growth of axons depends on protein synthesis [6,92–95].
Consequently, Campbell and Holt  showed that rapamycin
inhibited repulsive turning and collapse of axonal growth cones
of cultured retinal neurons of Xenopus caused by Semaphor-
in3A. A similar effect was observed during the “aversive”
response of axonal growth cones of Xenopus neurons to Slit
. The mTOR activity is also crucial for positive tropism of
axons towards a source of chemoattractant, netrin-1 . Since
incorporation of3H-leucine into newly synthesized proteins, in
response to chemorepellents, was blocked by rapamycin, even
when axons were separated from the cell body, local protein
synthesis was suggested as a major mTOR-regulated process
contributing to directional axonal growth . This hypothesis is
supported by the finding that addition of either chemorepellents
or chemoattractants induced local phosphorylation of mTOR
target—4E-BP1 in the axonal growth cones [6,94]. Which
proteins, synthesized in a mTOR-dependent fashion, regulate
axonal growth and directional turns of the growth cone? Since
growth of axons strongly depends on actin and microtubule
cytoskeleton dynamics , proteins involved in cytoskeleton
regulation are the likely targets. Indeed, Piper et al. 
presented evidence that both Semaphorin3A and Slit induce
local synthesis of the well-known actin depolymerizing protein,
cofilin . There are, however, a few other proteins, whose
translation is regulated by rapamycin, and previously shown to
be important for neurite and axonal growth, such as LIMK1,
mSec7-1 and Syndecan 3 (Table 1). But mTOR kinase can
regulate expression of proteins also at the transcriptional level.
Neuronal pentraxin 1 and ASH2L are both transcriptionally
regulated by mTOR [4,71]. These two proteins were also shown
to play a role in axonal development (Table 1). Finally, Rabex-
5, Ube2b and Sphingosine kinase 1 are neurite outgrowth
regulating proteins that were also identified in yeast screens for
genes that influence yeast growth in the presence of rapamycin
Dendritic arbor is the main site of information input onto
neurons, and different neurons have distinctive and character-
istic dendrite branching patterns. Advances in electrophysiol-
ogy and computational modeling have clearly shown that
121L. Swiech et al. / Biochimica et Biophysica Acta 1784 (2008) 116–132
dendritic arbor shape is one of the crucial factors determining
how signals from individual synapses are integrated [98,99].
Therefore dendritic arbor development is a process tightly
controlled by both external signals and intrinsic genetic
programs that involve activities of several kinases (reviewed
in [90,100–104]). Recent studies have added mTOR to the list
of kinases important for proper dendritic tree development
[7,8,105].Prolonged inhibition of mTOR activity due to chronic
(6 days) rapamycin treatment, or by means of RNA interference,
resulted in a decrease in the total number of dendritic branches,
and shrinkage of dendritic fields of hippocampal neurons
cultured in vitro [7,8]. The effect of mTOR inhibition on
dendritic tree complexity mimics the effect of inhibition of its
upstream activators, PI3K and Akt . Moreover, inhibition of
mTOR by the addition of rapamycin to cultured neurons also
blocked dendritic tree expansion induced by the overexpression
of BDNF, constitutively active Ras (Ras-CA), PI3K-CA, Akt-
CA, or the EGF family member CALEB/NGC [7,8,105].
How does mTOR contribute to dendritic arbor formation?
Available data corroborate the idea that control of protein
synthesis is the responsible mechanism. Jaworski et al. 
presented evidence that, like the effects of mTOR activity
inhibition, suppression of p70S6K activity by RNAi, as well as
overexpression of an 4E-BP1 constitutively active mutant,
resulted in both cases in a simplification of the dendritic trees of
hippocampal neurons cultured in vitro. Furthermore over-
expression of the constitutively active form of 4E-BP1 blocked
dendritic arborization induced by overexpression of PI3K .
However, individual proteins, which are translationally regulat-
ed by mTOR and are crucial for dendritogenesis, have not been
identified. Several groups screened for proteins translated
locally, in a mTOR-dependent manner, in the dendrites of
cultured neurons treated with BDNF, neurotransmitters or
insulin [29,81,106,107]. Several proteins identified by these
screens were previously shown to be important for dendritic
arbor growth (Table 1). The fact that many of them, like GRIP,
CamKIIα and β, subunits of glutamate receptors, PSD-95 and
Shank, are also important for synapse formation, is consistent
with the observation that synaptic activity is crucial for dendritic
arbor development [100,102,104]. Additional candidates be-
longing to this category, e.g., GABA receptor and additional
glutamate receptor subunits, can be regulated by mTOR at the
transcriptional level  (Table 1). Finally our recent work
suggests that physical interaction of mTOR and CLIP-170,
reported earlier in yeast and HEK cells , also occurs in the
brain, and that CLIP-170 is important for dendritic arbor
development (L.S. and J.J., unpublished). This observation
not only protein expression at different levels, but also other
cellular processes such as microtubule dynamics.
Excitatory synapses are formed at the tips of tiny mor-
phological structures protruding from dendritic shafts called
dendritic spines [108,109]. Dendritic spines are extremely
dynamic, both during development and in adulthood. Based on
experimental evidence, it is generally thought that longer spines
with smaller spine heads are more motile and plastic, and are
potential substrates for learning. On the other hand, spines with
relatively big heads and short necks (stubby and mushroom
type) are less motile and prone to change, and are therefore
believed to represent stable synapses. During development,
spine precursors called filopodia are initially formed, and then
convert to spines upon contact with presynaptic terminals. The
further fate of an individual spine depends on the activity of the
synapse it contains .
Kumar et al.  examined the effects of rapamycin on spine
number in cultured hippocampal neurons. Long-term (9 days)
application of the drug resulted in a decrease in both filopodia
and spine number. Moreover, mTOR inhibition prevented
MAPK and PI3K induced increase in filopodia number. Short-
term (24 h) downregulation of mTOR kinase activity also
prevented induced changes in spine and filopodia number.
Whereas, in control neurons, BDNF caused a decrease in spine
number, accompanied by an increase in number of filopodia,
addition of rapamycin for 24 h abolished neurotrophin effects
.However,applicationof rapamycin tocultured hippocampal
slices did not cause changes in the number of spines or filopodia
. The reasons for this discrepancy are not clear, but higher
morphological stability of neurons in slice cultures, due to better
preservation of the tissue structure, might be a simple
explanation. However, mTOR-related changes in spine mor-
phology could still be observed in this type of preparation, e.g.,
rapamycin treatment led to an increase of spine length .
Experimental induction of mTOR activity, by deletion of TSC
proteins, induced rapamycin-dependent spine head width
increase, on the other hand . This observation is consistent
with the data reported by Jaworski et al.  that overexpression
ofupstream regulators ofmTOR,PI3K andAkt inconstitutively
active form also led to an increase in spine head width. Proteins
that might contribute to the observed changes regulated by
mTOR are not known, but a few candidates are listed in Table 1.
3.2. mTOR and learning, memory and synaptic plasticity
Certain forms of long-lasting synaptic plasticity and memory
rely on protein synthesis [110,111]. Not surprisingly, TOR, one
of the major controllers of translation, is involved in long-term
synaptic plasticity in several organisms, including mammals
[13,89,112]. A recent review by Jaworski and Sheng 
discusses in detail the results of several electrophysiological
experiments addressing questions about mTOR function at the
synapse. Here we only briefly summarize the conclusions of
these studies, focusing rather on recent findings regarding
mTOR involvement in the processes of learning and memory,
hitherto not reviewed.
Long-term synaptic plasticity is defined as long-lasting
change (over several hours) in synaptic efficacy, measured as
the amount of current passing through the synapse to the
one. Two types of long-lasting synaptic plasticity can be
distinguished. One, when the synaptic connection becomes
stronger is called long-lasting long-term potentiation (L-LTP).
Second, long-term depression (LTD) occurs under certain
patterns of synaptic stimulation and results in weakened
122L. Swiech et al. / Biochimica et Biophysica Acta 1784 (2008) 116–132
synapses. Both, L-LTP (induced, for example, by prolonged
high-frequency synaptic stimulation, or BDNF) and metabo-
tropic glutamate receptor-induced LTD, are protein synthesis-
dependent and shown to require active mTOR ([11,13]; for a
review, see ). Vickers et al.  and Cracco et al. ,
who studied L-LTP in preparations of dendrites of hippocampal
neurons physically detached from the cell soma, confirmed the
importance of local protein synthesis for long-lasting synaptic
There is mounting evidence that molecular processes crucial
for synaptic plasticity in electrophysiological models are also
vital for processes of learning and memory. The first
observation of mTOR importance for long-term memory is
that of Tischmayer et al.  on the discrimination of linearly
frequency-modulated tones in Mongolian gerbils. During this
behavioral test, animals must learn to discriminate two different
sequences of the tones to avoid noxious stimuli, arrival of which
is signalized only by one of these. Inhibition of mTOR in the
auditory cortex of tested animals, by means of localized
rapamycin injections shortly after training, prevented consoli-
dation of long-term memory. In line with this, Parsons et al. 
showed that fear-conditioning, behavioral training, during
which rodents learn to fear a new, neutral stimulus because of
its pairing with an aversive one, increased a mTOR-driven
phosphorylation of p70S6K in the amygdala, a brain structure
important for fear memory formation. Moreover, infusion of
rapamycin directly to the amygdala prevented both phosphor-
ylation of p70S6K and fear memory formation. Similarly,
Bekinschtein et al.  reported that the formation of fear
memory requires mTOR activity. Finally, Dash and coworkers
 demonstrated a correlation between glucose levels,
mTOR activation and formation of memory for spatial
information (spatial memory). They showed that, in the brain,
high glucose levels and application of ACIAR (5-aminoimida-
zole-4-carboxamide-1b-4-ribonucleoside), an AMPK activator,
increased and decreased levels of mTOR phosphorylated
p70S6K and 4E-BP1, respectively. The Morris water maze is
one of several behavioral tests to study spatial memory
formation, and during this training rodents learn to find an
escape platform, placed in a water pool, below the water
surface, using only visual spatial cues, placed around the pool.
Good animal performance during this test strongly depends on
proper hippocampus activity. A post-training infusion of either
ACIAR or rapamycin to the rat hippocampus led to long-term
memory impairment in this test . Administration of mTOR
activating glucose doses had opposite effects and enhanced rat
performance during Morris water maze test . Interestingly,
young rats lacking one copy of the TSC2 gene (TSC2+/−; Eker
mutation), not displaying morphological symptoms of tuberous
sclerosis (see below), did not exhibit obvious changes in
performance in basic variants of spatial memory tasks (Moris
water maze, radial maze) . However partial loss of TSC2
enhanced episodic-like memory of the TSC2+/− rats. Episodic
memory is often defined as a memory of events, times and
places in relation to the experience, or memory of experience
with “what, where and when” dimensions. When tested in
“delayed matching to place task”, a test that requires rats to
distinguish between the actual and previous (when) locations
(where) of the platform to escape (what) the water maze, only
TSC+/− rats were able to remember the new platform location
when consecutive trials of the test were separated by long time
intervals . Potential molecular mechanisms by which
mTOR can regulate synaptic plasticity are very broad (see ).
Analysis of RNAs, associated with polysomes in response to
BDNF in a rapamycin-dependent manner , identified
several proteins previously studied for their role in synaptic
plasticity and learning and memory, e.g., NMDA receptor
subunit NR1, Homer2, Pyk2, LIMK-1, e-NOS. Additional
proteins regulating synaptic plasticity, such as CamKIIα, PSD-
95 and Arc were also reported to be expressed in mTOR-
dependent fashion [81,106,107].
3.3. Food intake regulation by mTOR
brain control of food uptake has been recently described. Cota
et al.  showed that both active mTOR and active p70S6K
were expressed in the arcuate nucleus of the hypothalamus
(ARC), and that animals fasted for 48 h had significantly
decreased levels of mTOR activity in this brain area. Re-feeding
returned mTOR activity and p70S6K phosphorylation status to
control levels. To check whether mTOR controls food uptake,
fasted rats were injected intraventricularly with L-leucine, which
is known to induce mTOR activity, or with leptin, known for its
proanorectic effects . While control rats showed increased
food uptake and no loss of body weight, application of either L-
leucine or leptin resulted in severe proanorectic effects, such as
decreased food uptake after starvation and weight loss.
Furthermore, leptin, similarly to L-leucine, induced mTOR-
mediated phosphorylation of p70S6K in ARC neurons, and
application of rapamycin prevented this induction. The mTOR
time . Recently, Morrison et al.  showed that mTOR is
also involved in the control of feeding behavior also in response
to changing levels of amino acids. Rats kept on a low-protein
diet exhibited increased food uptake as well as high expression
levels of agouti-related peptide (AgRP) mRNA. AgRP is a short
peptide known for its regulatory effect on feeding and body
weight control(see ).Prolongedadministration ofAgRPin
rodents was shown to cause obesity . Using GT1-7 hypo-
thalamic cells in culture, Morrison et al. , further showed
that acute exposure of cells to elevated concentration of amino
acids increased p70S6K phosphorylation and decreased AgRP
mRNA expression. However, the presence of rapamycin
antagonized both effects, even upon exposure of GT1-7 cells
to high amino acids levels. Taken together, these data suggest a
novel molecular mechanism where amino acids and hormones
canactwithinthebrain toregulatefooduptake,using mTORfor
control of Agrp expression.
Above, we discussed several examples of mTOR involve-
ment in the physiology of the nervous system. Whenever
possible, we tried to link experimental observations to potential
downstream cellular events, relying on available knowledge
about mTOR-regulated genes and proteins. However, there is a
123L. Swiech et al. / Biochimica et Biophysica Acta 1784 (2008) 116–132
need for a more systematic approach, and major experimental
effort, in our opinion, should be put now in identification of
mTOR targets, in neurons undergoing various physiological
processes (for example, stages of differentiations, various
neuronal plasticity paradigms), by phosphoproteomics, proteo-
mics and gene profiling. This definitely will help to define, in
detail, activities of mTOR in neurons, and such knowledge is
indispensable for further progress in understanding the role of
mTOR in neuronal physiology. It is also of importance for
revealing mTOR engagement in nervous system pathologies.
4. mTOR-related pathologies of the nervous system
Deregulation of mTOR signaling has been implicated in
several diseases, especially different types of cancer, including
brain tumors, particularly those involving mutations in genes
encoding upstream regulators of mTOR activity, such as PI3K,
Akt or PTEN. Since several reviews have appeared in this area
[18,121–124], we rather focus here on still underinvestigated
correlations between disturbances in mTOR activity in multi-
organ diseases affecting also the brain, and neurodegenerative
disorders. We also discus the possibility that mTOR signaling is
decreased in schizophrenia.
4.1. Multiorgan diseases
One of the best studied mTOR-related diseases that affect the
brain (besides other organs) is dominantly inherited tuberous
sclerosis (TSC). The direct causes of this disease are mutations
in genes on chromosomes 9q34 and 16p13 encoding hamartin
and tuberin, respectively (Fig. 2A) . An upregulation of
mTOR activity has been reported in tissues of TSC-affected
individuals . The brain hallmarks of the TSC are
hamartomatous brain lesions including cortical tubers, sub-
ependymal nodules (90% of cases) and subependymal giant cell
astrocytomas (SEGA, 5–15% of cases). The SEGAs display a
tendency to grow, which increases brain lesions and eventually
leads to increased intracranial pressure and death. Most of the
TSC patients have seizures (90% of affected individuals) and
are mentally retarded (60% of patients). Currently it is believed
that lesions caused by tubers, cellular hypertrophy and posi-
tioning of hamartomas are the source of the observed phe-
notype. Studies with animal models of this disease showed that
inhibition of mTOR activity by rapamycin or its analogs could
counteract disease development .
Rapamycin might also be a quite efficient for therapy of
hallmark of this disease is the development of benign and
malignant tumors of the nerve tissue and frequently cognitive
function impairment. The major reason of NF1 development is
loss of function mutation in the NF1 gene coding for
neurofibromin, that is Ras GAP. Recently, Johannessen et al.
 reported that mTOR signaling is upregulated in cells
signaling pathway and downregulation of tuberous sclerosis
complex activity (Fig. 2B). Indeed, addition of rapamycin
efficiently prevented growth of transformed Nf1−/−cells .
Aberrant mTOR activation in the brain was also described in
other diseases that affect normal brain morphology, some of
which are genetically linked. Puffenberger et al. , studying
Amish andMennonite patients, foundthat homozygousdeletion
of gene LYK5 leads to polyhydramniosis, megalencephally and
symptomatic epilepsy syndrome (PMSE syndrome). In addition
to other symptoms, all the affected patients displayed macro-
cephally and severe seizures. Postmortem analysis of the brain
tissue revealed existence of enlarged and dysmorphic neurons
and an increased mTOR-dependent phosphorylation of p70S6K
in several brain areas. This is consistent with a cellular role of a
STE20-related protein encoded by the LYK5 gene, which is a
crucial binding partner of LKB1, an indirect negative regulator
of mTOR activity.
The dysplastic and enlarged cells, similar to those described
for TSC, can also be found in the brains of individuals affected
by different forms of cortical displasia (CD). CD is a malfor-
mation of the cerebral cortex characterized by disturbed orga-
nization of cellular cortical layers, a cause of severe epilepsy.
Although a genetic cause has not been found for CD, recent
studies identified increased levels of phosphorylated Akt and
p70S6 kinase in dysmorphic, enlarged neurons with disturbed
axons and dendrites (cytomegalic neurons) found in the brains
of patients with different forms of CD, suggesting mTOR in-
volvement in this pathology .
4.2. Neurodegenerative disorders
Several lines of evidence suggest that mTOR signaling might
also be disturbed in several neurodegenerative disorders
including Parkinson's disease (PD), Alzheimer's disease (AD),
and Huntington's disease (HD) (Fig. 2C, D). All of them are
characterized by a gross neuronal loss in certain brain areas.
mRNA encoding RTP801 was identified as a highly
upregulated transcript in PC12 cells treated with 6-hydroxydo-
pamine (6-OHDA), N-methyl-4-phenylpyridinium cation
(MMP+) or rotenone, all of which are PD mimetics [20,129].
Application of 6-OHDA leads to increased cell death and
inhibition of mTOR-dependent p70S6K phosphorylation.
RTP801 protein is known for its ability to induce TSC1/2
activity  and along this line cells transfected with siRNA
against tuberin displayed increased survival rate and level of
phospho-p70S6K . Increased levels of RTP801 expression
were also found in dopaminergic neurons of substantia nigra of
Parkinsonian brains, and animals treated with 6-OHDA .
Interestingly, it was demonstrated recently that mTOR activity
inhibition by rapamycin resulted in a decreased expression of
Engrailed 1 transcription factor, which is a protein crucial for
dopaminergic neuron survival [131–133]. Indeed, mice lacking
Engrailed1 gene develop motor deficits similarly to PD patients
[131,132]. These two observations, taken together, could
corroborate a hypothesis that mTOR inhibition under PD con-
ditions results in downregulation of proteins crucial for neu-
ronal survival. However, rapamycin itself does not trigger PC12
death as does RTP801 . This may suggest that cell death is
a consequence of inhibition of non-rapamycin dependent (i.e.,
protein synthesis independent) activities of mTOR. Indeed,
124L. Swiech et al. / Biochimica et Biophysica Acta 1784 (2008) 116–132
Fig. 2. Deregulation of mTOR kinase activity in human neuropathology. (A) Tuberous sclerosis. (B) Neurofibromatosis 1. (C) Alzheimer's disease. (D) Parkinson's
disease. (E) Huntington's disease and therapeutic strategies for proteinopaties. See text for details. arrows and oval arrows—activation and inhibition of target protein
or cellular process, respectively; green and red arrows—increase and decrease of protein activity, respectively.
125L. Swiech et al. / Biochimica et Biophysica Acta 1784 (2008) 116–132
mTORC2 inhibition would lead to downregulation of activity of
a major prosurvival kinase, Akt . But, as mentioned above,
it is not clear what is the effect of downregulation of TSC2 on
mTORC2 activity . Alternatively RTP801 might act via an
additional unidentified mechanism. Which of the three sce-
narios is relevant for PD remains to be established. It is
noteworthy that overexpression of RTP801 increases sensitiv-
ity of neuroblastoma cells to another neurodegenerative
mimicking condition—cell exposure to β-amyloid (Aβ, see
The picture of mTOR activity regulation in Alzheimer's
disease is even more complicated than in the case of PD. Part of
the research on mTOR involvement in Alzheimer's disease
re-entrance. A decrease in the level of protein synthesis has been
described in the brain of AD patients , leading to the
hypothesis that hypoactivation of mTOR signaling might be one
of the important components of the pathology (Fig. 2C).
Accordingly, evidence was presented for inhibition of mTOR
activity in cultured neurons exposed to the Aβ, and in the brains
of transgenic animals carrying mutated variants of genes en-
coding presenilin 1 (PS-1; M146 to L mutation) and amyloid
precursor protein (APP; Swedish and London mutations), that
are cellular and animal models for AD, respectively . At the
molecular level, these findings can be explained by positive
effects of PS-1 on PI3K activity . Indeed, in animal models
of AD that carry the transgene encoding mutated PS-1 (M146 to
L mutation), mutation in the PS-1 gene was primarily res-
ponsible for the inhibition of mTOR activity . The mTOR
pathway activity was also downregulated in lymphocytes of AD
patients [22,138,139], which correlated with their memory and
emotional deficits [138,139].
On the other hand, levels of certain proteins in the brain
increase in the course of Alzheimer's disease (for example Tau).
Moreover, An et al.  and Li et al.  reported increased
levels of mTOR pathway activity in brain sections from AD
patients. This led to the concurrent hypothesis that mTOR
activity actually increases during AD and leads to elevation of
translation levels of toxic proteins (Fig. 2C). Indeed, there is
evidence that induction of the mTOR pathway activity precedes
accumulation of overwhelmingly translated Tau in neuroblasto-
ma cells and hippocampal neurons exposed to a high zinc
concentration (Zn2+increased levels are characteristic for AD
pathology) . An alternative order in the chain of events was
recently proposed by Khurana et al. , who showed, in a
Drosophila model of taupathology, that hyperphosphorylation
of Tau is rather a trigger than the cause of activation of dTOR.In
this model, Tau-induced TOR activation leads to activation of
the cell cycle regulators that ultimately induce neuronal cell
death (Fig. 2C). It is difficult to draw a conclusive picture of
mTOR activity impairments in AD because the use of different
disease models (PS-1/APP transgenic mice and Aβ-treated cells
vs. zinc exposed cells vs. Tau transgenic flies), and various
tissues of the AD patients (lymphocytes vs. brain postmortem
sections) preclude direct comparisons.
Studies of mechanisms underlying Huntington's disease
revealed that mTOR is sequestered by aggregates of mutated
huntingtin with expanded polyglutamine tracts and its activity is
diminished, both in cells cultured in vitro and in the brains of
transgenic animals (Fig. 2E) . Further examination of this
phenomenon showed that proteins with polyglutamine expan-
sions induce autophagy, most probably due to mTOR inhibition
(Fig. 2E). This inhibition leads to slower aggregate accumula-
tion and aggregate-related neurotoxicity . Indeed, Raviku-
mar et al.  showed that inhibition of mTOR by of CCI-779
in Ross/Borchelt mice expressing mutated huntingtin before
disease onset, prevents disease progress. Rubinsztein's group
presented evidence that rapamycin can reduce aggregation and
toxicity of other aggregate-prone proteins such as ataxin, Tau
and α-synuclein. The aggregation of these proteins is linked to
the spinocerebral ataxia, AD and PD, respectively [21,142,143].
These findings have raised hopes that inhibitors of mTOR can
be used to enhance autophagy in the course of anti-neu-
rodegenerative disease therapies  (see also Section 5).
4.3. Potential mTOR links to schizophrenia
Schizophrenia is linked with changes in the expression levels
of several genes. Indeed hypoactivity of upstream regulators of
mTOR activity, Akt and PI3K, was shown to correlate with
schizophrenia . The Akt1 gene on chromosome 14q22-32
has a linkage to schizophrenia and Akt1 expression was shown
to be downregulated in schizophrenic patients (for a review, see
). A decrease in expression of the p110α catalytic subunit
of PI3K was reported in lymphocytes of schizophrenic patients
. Several other proteins, aberrant expression of which has
been linked to diseases like Neuregulin-1 or dysbindin, are
known to mediate their actions, at least partially, through PI3K
and Akt . Strikingly, several therapies used for schizo-
phrenia treatment result in upregulation of PI3K-Akt signaling
. Whether mTOR might “suffer” due to insufficient PI3K-
Akt activity in the course of schizophrenia still needs to be
established. However, the observation that several neurons in
schizophrenics' brain tissue have smaller cell soma size, and
display subtle reductions in dendritic arborization and spine
number, is highly reminiscent of the phenotype of neurons
lacking mTOR activity [7,8].
A brief description of current progress in understanding the
consequences of altered mTOR activity in various nervous
system diseases, discussed above (Section 4), demonstrates that
we are still far from reaching this aim. While more accurate
animal models of the several nervous system diseases are
available, and novel methods of gene manipulation in neurons
in vivo are being constantly developed (see for example )
the most urgent requirement is to experimentally establish how
changes in the mTOR pathway contribute to disease progress.
This should also help to test mTOR as a potential target for
5. Perspectives for application of the mTOR inhibitors in
the nervous system—promises and caveats
Rapamycin and its analogues (AP-23573; RAD001; CCI-
779) could be potential therapeutics in multiple human diseases
126L. Swiech et al. / Biochimica et Biophysica Acta 1784 (2008) 116–132
(Table 2). Rapamycin has been used as an anti-rejection drug for
kidney transplants for the last 10 years and is approved for
treatment in cardiovascular diseases (drug-coated stents)
[147,148]. Another mTOR inhibitor, temsirolimus, has just
been approved for treatment of renal cell carcinoma [149–151].
mTOR inhibitors could be used to treat other diseases, including
tuberous sclerosis  and related disorders, e.g., renal angio-
myolipomas . Moreover, rapamycin and its analogues are
being considered for treatment of others types of cancer,
cardiovascular diseases, cardiac hypertrophy, age-related dis-
eases, autoimmune disorders, diabetes, obesity and neurological
disorders [154–158]. Since this review focused on the mTOR
activities in the nervous system, in the last paragraph we will
focus on the promises and caveats of the use of rapamycin and
its analogues for the neurodegenerative disorder treatment.
Several recent discoveries suggested that inhibition of
mTOR might be a strategy to slow down progress of
neurodegenerative disorders [21,142]. A common theme in
these disorders is aggregation of pathological proteins—
amyloid β and hyperphosphorylated Tau, α-synuclein, hun-
tingtin, ataxin in AD, PD, HD and ataxia, respectively .
Process of aggregate clearance from the cell can be accelerated
by increasing the rate of autophagy by mTOR inhibition
[21,142]. Therefore mTOR inhibitors have been seriously
considered as drugs of choice for disease treatment. One
obvious advantage is that several of them have been approved
for human treatment or are at different stages of clinical trials.
Severe neurological problems due to use of mTOR inhibitors
have hitherto not been reported. Moreover, at least one, CCI-
779, has been shown to be quite efficient in preventing mutated
huntingtin aggregation in animal models of HD . However,
several questions must be addressed. For example, autophagy
can decrease aggregates of Tau, but it can also induce higher Aβ
levels . Moreover, it is not clear whether soluble forms of
toxic proteins are more devastating to the cells than their
aggregates . It is also obvious that, prior to therapy,
contradictions concerning the mTOR pathway activity (as in the
case of AD) have to be resolved. Finally, since mTOR is
important for neuronal survival , development and proper
synaptic plasticity, one must consider that prolonged mTOR
inhibition may also impair these processes. A better under-
standing of downstream molecular mechanisms of mTOR
actions in neurons could contribute to developing more accurate
pharmacological interventions. The search for drugs, which
positively regulate autophagy without affecting the mTOR
pathway , may serve as a good example of such a strategy.
6. Conclusion and perspective
Our understanding of the role of mTOR in physiology of
developing and differentiated neuronal cells is presently
dramatically increasing. Considerable progress is also being
reported on the changes in mTOR activity accompanying brain
disease. However, we are still far from understanding how
modifications in mTOR activity contribute to disease progress.
An important aspect still missing, and urgently required, is
identification of downstream mTOR effectors in the nervous
system. This would lead to a better understanding of neuronal
use of mTOR inhibitors for clinical purposes. Increasing acces-
sibility of large screening methods in neurobiological studies
should assist in filling this gap in our understanding of mTOR
signaling in neurons.
We thank Prof. David Shugar for the invitation to present this
topic at the IPK2007 conference in Warsaw. The authors
appreciate comments on the manuscript by Prof. Shugar, Prof.
Kaczmarek and Dr. Bochtler. This work was supported by the
Polish Ministry of Science and Higher Education grant no.
PBZ-MNiI-2/1/2005 to J.J.
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mTOR inhibitors under clinical trials
(Rapamune); company: Wyeth
– Kaposi sarcoma
– Recurrent malignant gliomas
(combination with EGFR)
– Liver transplants (III phase)
– Acute myelogeneus leukemia
– Skin cancer
– Non-small cell lung cancer
– Renal cell carcinoma
– Advanced sarcomas (phase II completed)
– Solid tumors (in combination—phase I
completed; single agent—phase II)
– Hematologic malignancies (phase II)
– Drug-coated stents (preclinical phase)
– Phase I and II trials in multiple tumor
types, including breast, neuroendocrine and
gastrointestinal stromal tumor, nonsmall
cell lung cancer, metastatic renal cell
– Kidney and liver transplantation
– Mantle cell lymphoma (phase III)
– Malignant gliomas
– Solid tumors (phase I)
– Breast cancer (phase II compl.)
– Melanoma (phase II compl.)
– Drug-coated stents (preclinical phase)
AP-23573; company: Ariad
(Certican); company: Novartis
(Torisel); company: Wyeth
Zotarolimus; company: Molcan
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