The role of autophagy-lysosome pathway in
neurodegeneration associated with Parkinson’s disease
Tianhong Pan,1Seiji Kondo,2Weidong Le1and Joseph Jankovic3
1Parkinson’s Disease Research Laboratory, Baylor College of Medicine,2Department of Neurosurgery,University of Texas
M.D. Anderson Cancer Center and3Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology,
Baylor College of Medicine, Houston,TX,USA
Correspondence to: Joseph Jankovic, MD, Professor of Neurology, Director, Parkinson’s Disease Center, and Movement
Disorders Clinic, Baylor College of Medicine, Department of Neurology, 6550 Fannin #1801Houston,TX 77030,USA.
The ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP) are the two most important
mechanisms that normally repair or remove abnormal proteins. Alterations in the function of these systems to
degrade misfolded and aggregated proteins are being increasingly recognized as playing a pivotal role in the
pathogenesis of many neurodegenerative disorders such as Parkinson’s disease. Dysfunction of the UPS has
been already strongly implicated in the pathogenesis of this disease and, more recently, growing interest has
been shown in identifying the role of ALP in neurodegeneration. Mutations of a-synuclein and the increase of
intracellular concentrations of non-mutant a-synuclein have been associated with Parkinson’s disease pheno-
type.The demonstration that a-synuclein is degraded by both proteasome and autophagy indicates a possible
linkage between the dysfunction of the UPS or ALP and the occurrence of this disorder.The fact that mutant
a-synucleins inhibit ALP functioning by tightly binding to the receptor on the lysosomal membrane for auto-
phagy pathway further supports the assumption that impairment of the ALP may be related to the develop-
ment of Parkinson’s disease. In this review, we summarize the recent findings related to this topic and discuss
the unique role of the ALP in this neurogenerative disorder and the putative therapeutic potential through ALP
Keywords: autophagy-lysosome pathway; neurodegenerative disease; neuroprotection; Parkinson’s disease;
Abbreviations: ALP=autophagy-lysosome pathway; Ambra1=activating molecule in beclin1-regulated autophagy;
BafA1=bafilomycin A1; CMA=chaperone-mediated autophagy; HDAC6=histone deacetylase 6; IMPase=inositol
monophosphatase; mTOR=mammalian target of rapamycin; PI3K=phosphatidylinositol 3-kinase; PTEN=phosphatase and
tensin homologue; 3-MA=3-methyladenine;UPS=ubiquitin-proteasome system.
Received July 24, 2007 . Revised October19 , 2007 . Accepted December1 1 , 2007 . Advance Access publication January10, 2008
Normal balance between the formation and degradation
of cellular proteins is required for cell survival. The
pathways by which most cytosolic and misfolded proteins
are degraded are carried out by ubiquitin-proteasome
system (UPS) and autophagy-lysosome pathway (ALP)
(Ciechanover, 2005; Rubinsztein, 2006). Impairment of
either of these systems may lead to the accumulation and
aggregation of proteins resulting in cellular toxicity and
eventual neurodegeneration as seen in Parkinson’s disease,
Alzheimer’s disease, Huntington’s disease, amyotrophic
lateral sclerosis and other related protein conformation
Recently, there has been a growing interest in identifying
the role of the ALP in neurodegeneration (Martinez-Vicente
and Cuervo, 2007). Defects in this pathway have been linked
to neurodegenerative diseases (Ravikumar et al., 2002, 2004),
cancer (Kondo and Kondo, 2006) and cardiomyopathy
(Nakai et al., 2007). Since the UPS has been already
doi:10.1093/brain/awm318 Brain (2008),131,1969^1978
? The Author (2008).Publishedby Oxford University Pressonbehalfofthe Guarantorsof Brain. Allrightsreserved.For Permissions, please email: email@example.com
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Rubinsztein, 2006), in this article we will focus on the ALP
and its unique role in Parkinson’s disease. We will also discuss
the putative therapeutic potential of autophagy upregulation.
neurodegenerative diseases in the elderly. Lewy bodies,
cytoplasmic inclusions that contain aggregated proteins and
degeneration of substantia nigra dopamine neurons repre-
sent the pathological hallmarks of the disorder (Taylor
et al., 2000; Braak et al., 2003; Lansbury and Lashuel, 2006;
McNaught and Olanow, 2006). Increasing numbers of
proteins, such as ?-synuclein, have been identified in Lewy
bodies, but their role in the pathogenesis of both sporadic
and familial Parkinson’s disease is not well understood
(Zarranz et al., 2004; Chua and Tang, 2006; Mizuta et al.,
2006). Mutations of ?-synuclein, such as A53T, A30P and
E46K (Polymeropoulos et al., 1997; Kru ¨ger et al., 1998;
Zarranz et al., 2004), and the increase of intracellular
concentrations of non-mutant ?-synuclein, such as triplica-
tion of the ?-synuclein gene, have been implicated in the
cause of the disorder (Singleton et al., 2003).
Beside excessive accumulation of misfolded proteins,
several lines of evidence have converged to suggest that
environmental neurotoxins, including herbicides, such as
paraquat, and other mitochondrial
rotenone, (Betarbet et al., 2000; Sherer et al., 2003),
mutant proteins such as DJ-1 (Bonifati et al., 2003),
PINK1 (Valente et al., 2004) and LRRK2 (West et al.,
2005), may contribute to mitochondrial dysfunction and
ofthe most common
poisons, such as
increase cellular oxidative stress, all of which have been
implicated in the aetiopathogenesis of Parkinson’s disease.
Increased oxidative stress, associated with depletion of ATP,
is considered to contribute to the reduction of proteasome
activity and aggregation of abnormal proteins (Norris and
Giasson, 2005; Abou-Sleiman et al., 2006; Lin and Beal,
2006; Schapira, 2006). Moreover, mutations of parkin
(Foroud et al., 2003; Kay et al., 2007) and UCH-
L1(Maraganore et al., 2004; Das et al., 2006), components
of the UPS and mutations of ATP13A2 that codes for a
lysosomal ATPase (Ramirez et al., 2006; Di Fonzo et al.,
2007) have also been shown to result in impaired protein
degradation. Thus, a failure of protein degradation caused
by various factors may lead to neuronal cell death related to
Parkinson’s disease and other neurodegenerative disorders
(Webb et al., 2003) (Fig. 1).
Protein clearance systems in Parkinson’s
The UPS is responsible for a highly selective degradation of
short-lived intracellular and plasma membrane proteins
under basal metabolic conditions, as well as misfolded or
damaged proteins in the cytosol, nucleus or endoplasmic
reticulum. The system involves the targeting of susceptible
proteins by ubiquitin and only the unfolded ubiquitinated
proteins can pass through the narrow pore of the
proteasome barrel. Dysfunction of the UPS and the
Fig.1 Causes of protein aggregation and dopaminergic neuron death.Multiple factors, such as genetics, aging and environmental toxins, or
combinations, have beenimplicatedin the aetiology of Parkinson’s disease. All these may directly or indirectly affect the function of protein
degradation systems, including ubiquitin proteasome system (UPS) and autophagy-lysosome pathway (ALP), and thereby, cause the death of
1970Brain (2008),131,1969^1978T . Pan et al.
by guest on June 12, 2013
resultant accumulation of misfolded proteins have been
strongly implicated in the pathogenesis of Parkinson’s
disease (Larsen and Sulzer, 2002; McNaught et al., 2003;
Olanow and McNaught, 2006; Rubinsztein, 2006), which is
supported by molecular genetic studies of Parkinson’s
disease-causing genes, including ?-synuclein, parkin and
UCH-L1 (Foroud et al., 2003; Maraganore et al., 2004; Das
et al., 2006; Kay et al., 2007). Parkin mutations in
autosomal recessive juvenile
decrease in ubiquitin-ligase enzymatic activity in the
substantia nigra (Shimura et al., 2000, 2001), which also
support the hypothesis that failure of the UPS leads to the
neurodegeneration underlying Parkinson’s disease.
The ALP can be divided into three distinct pathways based
on the ways substrates reach the lysosomal lumen:
macroautophagy (generally referred to as autophagy),
(CMA) (Cuervo et al., 2004; Levine and Klionsky, 2004)
(Fig. 2). Autophagy can be induced within short periods of
nutrient deprivation, and CMA can be induced after
prolonged nutrient deprivation, while microautophagy is
not activated by nutritional deprivation or stress. In
autophagy is likely to be the primary mechanism involved
in the degradation of long-lived, stable proteins and is the
only mechanism by which entire organelles such as
mitochondria are recycled. Large membrane proteins and
protein complexes (including oligomers and aggregates)
that fail to pass through the narrow proteasome barrel can
be degraded by autophagy (Klionsky and Emr, 2000;
Cuervo et al.,2004; Levine
Hideshima et al., 2005).
Autophagy is a multi-step process, involving the forma-
tion of double membrane structures known as autophago-
somes. Later, the autophagosome fuses with lysosomes to
form autophagolysosomes, where their contents are then
degraded by hydrolytic enzymes. The autophagosome and
autophagolysosome are collectively referred to as autopha-
gic vacuoles, which are considered to be the characteristic
components of autophagy (Takeuchi et al., 2005). Finally,
the inner membrane structure within the autophagolyso-
some disintegrates while its contents are digested, and the
vacuolar contents are recycled to provide amino acids and
energy as needed by the cells (Fig. 2). Microautophagy is
cytosolic proteins, pinched off from the lysosome mem-
brane even under resting conditions. CMA is a secondary
response that temporally follows autophagy. In CMA, a
specific cytosolic protein–molecular chaperone (heat-shock
cognate protein of 70kDa, hsc70) complex binds to the
transported into lysosomes for degradation by hydrolases
(Crotzer and Blum, 2005).
There are many steps at which the dysfunction of the ALP
may occur, including the failure of autophagosome forma-
tion or autophagosome fusion with lysosomes, deficiency of
enzymes in lysosomes and the dysfunction of the molecular
charperone or lysosomal membrane receptor, any of which
may consequently cause the aggregation of unwanted
proteins leading to the death of cells.
Autophagy is an important process in a variety of human
diseases caused by toxic, aggregate-prone, intracytosolic
lamp2a, andis then
Fig. 2 Autophagy-lysosome pathway (ALP) in mammalian cells.Generally, the cytosolic proteins and cell components are degraded
through macroautophagy pathway. Inhibition of the autophagosome formation by 3-methyladenine (3-MA) without markedly affecting
protein synthesis or ATP levels (Seglen and Gordon,1982), or inhibition of the fusion of autophagosome with lysosome by bafilomycin A1
(BafA1) through inhibiting vacuolar type H+-ATPase (V-ATPase), may lead to the dysfunction of macroautophagy. In microautophagy, the
lysosomal membrane itself deforms to engulf the cytosolic substrates. Specific cytosolic proteins that can be recognized by a cytosolic
chaperone, the heat-shock cognate protein of 70kDa (hsc70), which targets them to the surface of lysosomes, may be degraded through
Autophagy and Parkinson’s diseaseBrain (2008),131,1969^1978 1971
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proteins, which become inaccessible to the proteasome
when they form oligomers (Ravikumar et al., 2002, 2004;
Webb et al., 2003; Rubinsztein et al., 2007). It has been
reported that suppression of the basal autophagy gene Atg5
(autophagy-related gene 5) or Atg7 (autophagy-related gene
7) in the CNS leads to accumulation of polyubiquitinated
proteins with neurodegeneration in mice (Kuma et al.,
2004; Hara et al., 2006; Komatsu et al., 2006; Massey et al.,
2006) and increases the susceptibility to certain types of
apoptosis (Larsen and Sulzer, 2002; Boya et al., 2005;
Ravikumar et al., 2006), further providing the evidence that
there is a relationship between autophagy deficiency and
the development of neurodegenerative diseases. One of the
examples for neurodegeneration caused by deficiency of
enzymes in lysosomes is lysosome storage disorder, which is
an inheritedmetabolic disease,
abnormal build-up of various toxic materials in the cells
as a result of the lysosomal enzyme deficiencies (Fukuda
et al., 2006; Kiselyov et al., 2007) (Table 1).
Involvement of ALPin Parkinson’s disease
Mutations of ?-synuclein and the increase of intracellular
concentrations of non-mutant ?-synuclein have been
implicated in the pathogenesis of Parkinson’s disease
(Polymeropoulos etal., 1997;
Singleton et al., 2003; Zarranz et al., 2004). In addition to
the UPS, ?-synuclein is also cleared by autophagy (Webb
et al., 2003; Cuervo et al., 2004; Lee et al., 2004;
Bandhyopadhyay and Cuervo, 2007), which supports the
?-synucleins is an important mechanism of neurodegenera-
tion in Parkinson’s disease (Cuervo et al. 2004).
Furthermore, it has been shown that wild-type ?-synuclein,
but not the mutant ?-synuclein, is selectively translocated
into lysosomes for degradation by the CMA pathway (Cuervo
et al., 2004). The failure of CMA to clear mutant ?-synucleins
may be explained by their exceptionally high affinities for the
lysosomal membrane receptors that mediate the autophagy
pathway as compared with the wild-type ?-synucleins
(Cuervo et al., 2004). The binding of mutant ?-synucleins
Kru ¨geret al., 1998;
autophagic degradation of
to the receptors probably blocks the lysosomal uptake and
inhibits the degradation of not only mutant ?-synucleins, but
also other CMA substrates. Although the blockage of CMA
could potentially result in a compensatory activation of other
degradation pathways, these auto-activated pathways may
not be able to sustain efficient rates of protein degradation.
Thus, the accumulated mutant ?-synucleins and other
substrates further perturb cellular homoeostasis and con-
tribute to neuronal toxicity.
The findings that lysosomal malfunction accompanies
?-synuclein aggregation in a progressive mouse model
(Meredith et al., 2002), and that mutations in ATP13A2, a
lysosomal ATPase, lead to a failure of autophagy execution
and aggregation of ?-synuclein in Parkinson’s disease
(Ramirez et al., 2006; Di Fonzo et al., 2007) further
support the hypothesis that ALP dysfunction is an
important mechanism of neurodegeneration.
In addition to the primary causes of ALP dysfunction
already discussed, aging may be another important factor
related to the dysfunction of protein control systems since
it has been found that the activities of both the UPS and
ALP are decreased in almost all old organisms (Keller et al.,
2004; Cuervo et al., 2005; Martinez-Vicente et al., 2005;
Kiffin et al., 2007). Since age is one of the chief risk factors
for Parkinson’s disease (Dauer and Przedborski, 2003;
Jankovic, 2005; Nagatsy and Sawada, 2006), it is reasonable
to postulate that the aging brain is particularly vulnerable
to dysfunction of the ALP.
Auto-regulation ofautophagyin Parkinson’s disease
Alterations of the UPS have been implicated in the
pathogenesis of Parkinson’s disease. Along with ubiquiti-
nated protein aggregates, affected neurons often contain
structures related to autophagy. For example, an increased
number of autophagic vacuoles and related structures of
autophagy have been found in Parkinson’s disease patients
(Anglade et al., 1997), animal models of Parkinson’s disease
(O¨ztap and Topal, 2003) and in other disorders, including
Huntington’s disease (Sapp et al., 1997; Kegel et al., 2000;
Petersen et al., 2001) and Alzheimer’s disease (Nixon et al.,
T able1 The pathogenesis and autophagy in some of the PCDs and LSDs
Number of AVEffect of autophagy
Parkinson’s diseaseAggregation of ?-synuclein mutants
(A53T, A30P, E46K)
Aggregation of mutant huntingtin
UPS and ALP Increased in
Enhance degradation of
Reduces the toxicity of
Compensate for the defects
in lysosome function caused by
deficiency of lysosomal enzymes
Huntington’s diseaseUPS and ALP
Alzheimer’s diseaseAggregation of neurofibrillary tangles,
b-amyloid-containing neuritic plaques
Aggregation of mutant SOD1
UPS and ALP
UPS and ALP?
Accumulation of substrates targeted
by lysosomal enzymes that are
PCD=protein conformation disorder; ?=not clear/not known.
1972Brain (2008),131,1969^1978 T . Pan et al.
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2005; Butler and Bahr, 2006; Zheng et al., 2006) (Table 1).
This increase in autophagic markers raises the argument
whether autophagy is a cause or a protective factor of
neuron death. It has been suggested that the increased
number of autophagic vacuoles is responsible for the
neuronal cell death, but an alternative view is emerging
that autophagy is induced to protect neurons by enhancing
degradation of abnormal proteins that might trigger injury
or apoptosis in the early stages of cell death (Butler et al.,
2006; Bandhyopadhyay and Cuervo, 2007).
Several lines of evidence suggest that once the UPS is
inhibited, autophagy is upregulated and the remaining
aggregated proteins are degraded (Iwata et al., 2005; Massey
et al., 2006). Thus, this is considered to be a default
pathway when an aggregate-prone substrate cannot effi-
ciently be cleared by the proteasome (Rideout et al., 2004;
mechanism that accelerates the degradation of misfolded
proteins as a defence or protection may be one of the
explanations of the increased number of autophagic
vacuoles in the brains of Parkinson’s disease patients
(Anglade et al., 1997), possibly in response to dysfunction
of the UPS (Fig. 3). However, with pathogenic deteriora-
tion, this compensatory auto-regulative mechanism is
ultimately unable to maintain the cellular balance and
eventually results in neuronal death (Trojanowski and Lee,
2000). This auto-regulative concept to explain the increased
the number of autophagic vacuoles is also supported by the
finding that autophagic structures occur in the early stage
of the MPTP-injected mouse model of Parkinson’s disease
(O¨ztap and Topal, 2003) and in a progressive mouse model
of Parkinson’s disease with lysosomal malfunction accom-
panied by ?-synuclein aggregation (Meredith et al., 2002).
A recent report has shown that histone deacetylase 6
(HDAC6) is an essential mechanistic link in this compen-
satory induction of autophagy when the UPS is impaired in
Drosophila melanogaster (Pandey et al., 2007).
The mitochondrial toxin paraquat (1, 10-dimethyl-4,
40-bipyridinium dichloride), a widely used herbicide, is
thought to be a putative aetiological factor in the develop-
ment of Parkinson’s disease. The facts that paraquat induces
the accumulation of autophagic vacuoles and increases the
degradation of long-lived proteins in the cytoplasm of human
neuroblastoma SH-SY5Y cells (Gonzalez-Polo et al., 2007a)
indicate that enhanced oxidative stress possibly actives
autophagy during the early stage of mitochondrial dysfunc-
tion and helps to resist the enhanced oxidative stress
(Gonzalez-Polo et al., 2007b). It seems that autophagy is
induced in the early stage and impaired in the later period of
the neurodegerative process (Boland and Nixon, 2006;
Bandhyopadhyay and Cuervo, 2007).
Althoughcells can activate
mechanisms in response to various insults in order to
prevent or minimize damage, this is often not enough to
completely avoid injury to cells. Strategies focusing not only
on ameliorating the symptoms of Parkinson’s disease, but
also on neuroprotection, or neurorescue that can favourably
modify the natural course of the disease will be the most
important aspect of therapeutic development (Jankovic,
2006). Thus far, there are no effective therapies to slow or
prevent neuronal degeneration in this disorder. Since the
formation of inclusion bodies that contain the misfolded and
aggregated proteins is one of the its pathological features,
development towards the effective and safe targeting of
aggregate-prone proteins will be an important aim for
therapies in Parkinson’s disease (Eriksen et al., 2005).
Although dysfunction of the UPS has been implicated in
Parkinson’s disease, it is undesirable to upregulate protea-
some activity as a therapeutic strategy since proteasomes
degrade not only toxic proteins but also key short-lived
intracellular regulators (for example, the tumour suppressor
p53), whose steady-state levels are dependent on their
degradation rates. Enhancing the degradation of such
proteins may have deleterious consequences, such as
cancer in the case of p53. On the other hand, upregulating
autophagy may be beneficial, since in contrast to many UPS
substrates, autophagy substrates are typically long-lived
proteins and are not believed to be selectively degraded.
Autophagy has been largely recognized as an inducible
process because its activity can be regulated by nutrient or
growth factor-deprivation, stress or pathogenic invasion
(Levine, 2005; Kiffin et al., 2006). The autophagic activity is
maintained at low levels in the brain even with nutrient
starvation, a condition that usually induces autophagy in
most other organs (Mizushima et al., 2004); however,
neural cellshave the ability
in response to factors other than nutrient limitation.
Thus, autophagy enhancement might be a novel strategy
for the treatment of neurodegenerative disease (Menzies
Fig. 3 Autophagy compensates for impaired UPS function.
Proteasome inhibition-induced dysfunction of UPS leads to
neurodegeneration.When UPS is impaired, autophagy can
be compensatively induced to help remove the excessive
unwanted proteins caused by UPS dysfunction and rescues neuro-
degeneration.The activity of HDAC6, a microtubule-associated
deacetylase that interacts with poly-ubiquitinated proteins, is
essential for autophagy to compensate for impaired UPS function.
HDAC6 rescues neurodegeneration associated with UPS dysfunc-
tion in an autophagy-dependent manner (Pandey et al., 2007).
Autophagy and Parkinson’s diseaseBrain (2008),131,1969^19781973
by guest on June 12, 2013
et al., 2006). Utilizing different signalling pathways (Fig. 4),
autophagy may participate in cell growth, proliferation, cell
survival and death.
Enhancement of autophagy through the
m TOR-dependent pathway
Although various manipulations can be used in vitro to
upregulate autophagy, most of these strategies are not suitable
for clinical application. One pharmacological strategy for
upregulating autophagy in mammals, however, is to use
rapamycin or its analogues through the inhibition of
mammalian target of rapamycin (mTOR), a negative
Rapamycin has been reported to protect against huntingtin-
induced neurodegeneration in fly and mouse models of
Huntington’s disease through autophagy induction, indicat-
ing its therapeutic potential (Ravikumar et al., 2002, 2004,
2006; Berger et al., 2006; Rubinsztein, 2006). Also, rapamy-
cin-induced autophagy has been shown to degrade all forms
of ?-synuclein, as demonstrated in a stable inducible PC12
cell model (Webb et al., 2003), suggesting that it may be
considered as a potential therapeutic agent in Parkinson’s
disease. Furthermore, enhancement of autophagy by rapa-
mycin may have additional cytoprotective effects against a
range of subsequent pro-apoptotic insults (Pan et al., 2006;
Ravikumar et al. 2006; Williams et al., 2006). Thus, the drug
may work primarily by inducing autophagic degradation of
mutant aggregate-prone proteins and, therefore, may be
useful in neurodegenerative diseases that are associated with
an increased rate of apoptosis (Jankovic, 2005). Secondary
beneficial effects of rapamycin-induced autophagy may be an
enhanced clearance of mitochondria with a reduction of
cytosolic cytochrome c release and downstream caspase
activation (Ravikumar et al., 2006).
Although rapamycin has been used clinically as an
antibiotic and immunosuppressant without serious adverse
effects, long-term use of the drug as an inhibitor of mTOR
may potentially be associated with complications since the
mTOR proteins control several cellular processes, including
repression of ribosome biogenesis and protein translation,
and transcriptional induction of compensatory metabolic
pathways (Sarbassov et al., 2005).
Enhancement of autophagy through an
m TOR-independent pathway
Recent studies have identified novel small-molecule enhan-
cers (SMER) of mammalian autophagy, which boost the
clearanceof autophagysubstrates including mutant
Fig. 4 Signalling pathways in the regulation of autophagy. Autophagy is activated in response to nutrient starvation, differentiation and
developmental triggers. It is an adaptive process responding to metabolic stresses that results in degradation of intracellular proteins and
organelles.There are three classes of phosphatidylinositol 3-kinase (PI3K) in mammalian cells.Class I PI3K is an inhibitor of autophagy.
Stimulation of class I PI3K pathway through insulin receptor results in the activation of the mammalian target of rapamycin (mTOR),
thereafter, inhibits autophagy. Phosphatase and tensin homologue (PTEN) enhance the autophagy through the inhibition of class I PI3K.
Class IIIPI3Kis an activator of autophagy andplays a crucialrole at an early step of autophagosome formation.The beclin1/PI3K-III complex
is involved in the formation of autophagosomes and initiation of autophagy. Ambra1 (activating molecule in beclin1-regulated autophagy),
is a positive regulator of the beclin1-dependent programme of autophagy (Fimia et al., 2007). Autophagy is regulated through energy
metabolism. During the nutrient starvation or ATP deficiency due to mitochondrial complex I inhibition, autophagy is enhanced through
the mTOR pathway. At the sequestration step, 3-MA interferes with the activity of class III PI3K to interrupt autophagy (Blommaart et al.,
1997; Petiot et al., 2000).Wortmannin, LY294002 inhibit class III PI3K to reduce autophagy.Furthermore, neither wortmannin nor
LY294002 displays selectivity for different members of the class I PI3K. At higher concentrations, wortmannin inhibits PI3K-related
enzymes, such as mTOR. Rapamycin inhibits mTOR to induce autophagy. Mood-stabilizing drugs, such as lithium, carbamazepine and VPA,
induce autophagy through inhibition of inositol monophosphatase (IMPase), which is mTOR-independent pathway.
1974Brain (2008),131,1969^1978 T . Pan et al.
by guest on June 12, 2013
huntingtin and A53T ?-synuclein. These agents seem to act
either independently or downstream to the target of
rapamycin (Sarkar et al., 2007b).
Lithium, one of the mood-stabilizing drugs, can increase
the clearance of aggregate-prone proteins, including mutant
huntingtin and the A30P and A53T mutants of ?-synuclein
through induction of autophagy by inhibiting inositol
monophosphatase (IMPase) (Sarkar et al., 2005; Sarkar and
Rubinsztein, 2006). The stimulation of autophagy by
lithium is thought to involve a novel mTOR-independent
pathway by decreasing free inositol (Sarkar et al., 2005;
Sarkar and Rubinsztein, 2006). Since inositol depletion is a
common mechanism for mood-stabilizing drugs, including
lithium, carbamazepine and valproic acid, by enhancing
autophagy, these may have an important therapeutic
potential in the treatment of Parkinson’s disease.
In addition, trehalose, a disaccharide present in many non-
mammalian species, has been reported to enhance the
clearance of mutant huntingtin and the A30P and A53T
mutants of ?-synuclein and protect cells against various
environmental stresses through autophagy induction in an
Furthermore, the combination of trehalose and mTOR
inhibition by rapamycin has been shown to exert an additive
effect on the clearance of these aggregate-prone proteins
because of increased autophagic activity (Sarkar et al., 2007a).
(Sarkar et al.,2007a).
Deleterious effects of autophagy
The discovery of the molecular basis of autophagy has
uncovered its importance during development, life exten-
sion and in pathological conditions, such as cancer, certain
myopathies and neurodegenerative diseases. Besides, autop-
hagy may play an important cytoprotective role by
facilitating removal of protein aggregates before they
become toxic (Kuma et al., 2004; Baehrecke, 2005). In
addition, autophagy can function in cell death by execution
of self-killing programme of irreversibly injured cells
(Bursch, 2001; Dickson, 2007). In some extreme instances
of programmed cell death, cells can be completely degraded
demonstrates that late-stage neuronal cell loss generally
occurs via autophagy and it has been suggested that over
activation of autophagy in neurons is the eventual cause of
‘physiological’ death (Takacs-Vellai et al., 2006).
Autophagy has been linked to disease processes by various
morphological studies (Klionsky and Emr, 2000). Thus,
whether autophagy protects against disease or causes it may
depend on the specific situation and stage in the pathological
process (Rubinsztein et al., 2005). Although many issues
remain unclear, there is emerging evidence that abnormal
regulation of autophagic pathways may lead to apoptosis and
cell death (Degterev et al., 2005; Chu, 2006; Klionsky, 2006).
From a therapeutic viewpoint, it is not certain that
prolonged upregulation of autophagy would be without
risks because autophagy enhancement may cause a lower
steady-state level of mitochondrial load and a decrease in
Rubinsztein, 2006). However, the finding that the activities
of some respiratory complexes can be reduced by 25–80%
before respiration or ATP synthesis in brain mitochondria
are affected (Murphy, 2001) indicates that upregulation of
autophagy will not result in eventual total depletion of
mitochondria. It is, therefore, possible to induce autophagy
and reduce mitochondrial load to the levels that have
substantial protective effects against proteinopathies but do
not adversely affect cellular respiration. Hence, the ability to
maintain proper autophagic activity, rather than massive
upregulation of autophagy, should be the therapeutic goal
in diseases associated with protein aggregation.
and its dysfunction has emerged as a theme in neurodegenera-
tive disorders. It is believed that activating autophagy, which
may have beneficial effect on the clearance of misfolded and
aggregated proteins and preventionofneurodegeneration,may
become a new therapeutic target in neurodegenerative
disorders, such as Parkinson’s disease. However, due to the
to keep in mind that the regulation of autophagy is a very
delicate process. Inappropriate or prolonged activation of
autophagy may lead to the complete demise of the cells
involved. Thus, to determine when and for how long this
activation should be maintained will be another major
challengeinthe future development ofthe therapeutic strategy.
This work was supported by Diana Helis Henry Medical
Research Foundation (2007). We also thank the National
Parkinson Foundation of their support of the NPF Center
of Excellence at Baylor College of Medicine.
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