nature neuroscience VOLUME 13 | NUMBER 7 | JULY 2010
Although autophagy—the degradation of cytosolic components in
lysosomes—has been known for more than five decades, its impor-
tance in the central nervous system, and in neurons in particular, has
only recently been demonstrated1–4. The explosion of information in
the field of autophagy3 is leading to a better understanding of classic
neuronal disorders—in particular, those dealing with protein mis-
handling and problems in cellular quality control.
As the field advances, some chapters in our understanding of
autophagy are finally reaching closure. These include the initial
controversy over whether or not autophagy even occurs in neurons:
neuronal accumulation of autophagosomes has been described in
multiple brain disorders (reviewed in refs. 1,5,6), and it is clear that
neurons have the machinery and molecular components required
for conducting autophagy. Neurodegeneration and protein inclu-
sions have been described in mouse models incompetent to perform
autophagy in neuronal tissues7,8, making a strong case for a criti-
cal role of autophagy in maintenance of neuronal homeostasis and
protein quality control in neurons. More recent studies using simi-
lar genetic approaches have now confirmed an essential function of
autophagy in neuronal development and remodeling9–12.
In contrast, other topics, such as the nature of the autophagic defect
in different neurodegenerative disorders, are now making headlines,
and many studies and resources are dedicated to their detailed dis-
section. This review will focus on the different types of autophagic
dysfunction in neurodegeneration and the importance of identifying
the autophagic step(s) altered in each particular disorder for thera-
Autophagic pathways in neurons
Cellular quality control through autophagy is particularly relevant
in neurons, where the total content of altered proteins and dam-
aged organelles cannot be reduced by redistribution to daughter
cells by means of cell division. Neuronal surveillance mechanisms
must identify these malfunctioning structures and assure their
autophagic degradation before their intracellular buildup gives rise to
neurotoxicity5,6. Delivery of autophagic subcellular components to the
damaged structures must accommodate the unique neuronal archi-
tecture, whereby the cytoplasm can extend long distances through
the many projections from the cellular body and accommodate the
dynamic traffic to and from polarized neuronal projections. Besides
neuronal homeostasis, autophagy is also used for the continuous
remodeling of neuronal terminals that is required to support
neuronal plasticity9–12. On the basis of these prior observations, it
is not surprising that alterations in the autophagic system would be
intimately linked to different neuronal diseases.
The first clue of altered autophagy in different neurodegenera-
tive settings is often an abnormal number of autophagosomes in
the affected neurons13–15. However, expansion of this autophagic
compartment could come from the impairment in any of the
several steps of autophagy, and it only provides information on
macroautophagy, one of the subtypes of autophagy. In fact, the term
autophagy refers to the degradation of cytosolic components in
lysosomes independently of the mechanism by which the degraded
cargo is delivered to the lysosomal compartment. In most mamma-
lian cells, delivery occurs by three different means that distinguish
the subtype of autophagy: macroautophagy, microautophagy and
chaperone-mediated autophagy (CMA). The characteristics, regula-
tion and main molecular components of these autophagic pathways
have been reviewed in detail elsewhere1–3. Briefly, macroautophagy
and microautophagy involve the direct sequestration of whole areas
of the cytosol by invaginations at the lysosomal membrane (in the
case of microautophagy), or by a membrane that seals to form a
double-membraned vesicle, or autophagosome (in macroautophagy).
Microautophagic vesicles at the lysosomal membrane ‘pinch off’
into the lysosomal lumen, and cargo is degraded by the lysosomal
hydrolases upon digestion of the vesicles’ limiting membrane16. In
the case of macroautophagy, fusion between autophagosomes and
lysosomes mediates the delivery of the autophagic cargo into the
lysosomal lumen1,2. In the third common type of autophagy, CMA,
cargo is not sequestered but is instead selectively recognized by
a complex of cytosolic chaperones that mediates its delivery to a
receptor at the lysosomal membrane17,18. Cargo gains access to
Department of Developmental and Molecular Biology, Marion Bessin Liver
Research Center and Institute for Aging Studies, Albert Einstein College of
Medicine, Bronx, New York, USA. Correspondence should be addressed to
Published online 25 June 2010; doi:10.1038/nn.2575
Autophagy gone awry in neurodegenerative diseases
Esther Wong & Ana Maria Cuervo
Autophagy is essential for neuronal homeostasis, and its dysfunction has been directly linked to a growing number of
neurodegenerative disorders. The reasons behind autophagic failure in degenerating neurons can be very diverse because of the
different steps required for autophagy and the characterization of the molecular players involved in each of them. Understanding
the step(s) affected in the autophagic process in each disorder could explain differences in the course of these pathologies and
will be essential to developing targeted therapeutic approaches for each disease based on modulation of autophagy. Here we
present examples of different types of autophagic dysfunction described in common neurodegenerative disorders and discuss
the prospect of exploring some of the recently identified autophagic variants and the interactions among autophagic and non-
autophagic proteolytic systems as possible future therapeutic targets.
© 2010 Nature America, Inc. All rights reserved.
VOLUME 13 | NUMBER 7 | JULY 2010 nature neuroscience
the lysosomal lumen through a translocation complex, thus limit-
ing CMA to soluble proteins that can undergo complete unfolding.
All three autophagic pathways usually coexist in the same cell, and
alterations in both macroautophagy and CMA have recently been
associated to specific neurodegenerative disorders17.
The when and where of the macroautophagic halt
The detailed molecular characterization of macroautophagy and the
development of probes to track and methods to modulate this process
have been instrumental in our understanding of the physiological
functions of this pathway3. These advances have facilitated the iden-
tification of autophagic malfunction in many human disorders (a
complete description of the pathophysiology of macroautophagy
can be found in refs. 1,19,20), including a growing number of neuro-
logical disorders such as Alzheimer’s disease, Parkinson’s disease,
Huntington’s disease and amyotrophic lateral sclerosis (ALS)13,14,21–26.
Different findings in recent years have helped to consolidate a con-
nection between macroautophagy and neurodegenerative disorders
and have propelled the current interest in this topic. For example,
aggregates formed by some pathogenic proteins have proven amen-
able to degradation by macroautophagy22,27. In addition, pharmaco-
logical upregulation of macroautophagy has been shown effective in
reducing neuronal aggregates and slowing the progression of neuro-
logical symptoms in fly and mouse models of Huntington’s disease28.
These findings have generated a justifiable level of optimism and
have led to the idea that upregulation of macroautophagy might
represent a plausible therapeutic intervention in these disorders.
However, recent studies have added a note of caution concerning
the applicability of macroautophagy upregulation as a generalized
treatment. For example, inhibition, rather than stimulation, of macro-
autophagy increases neuronal survival in some pathological condi-
tions showing high content of neuronal autophagic vacuoles, such
as ischemic stroke15,29–31. How can block-
ing macroautophagy be beneficial when it
is the only pathway that can eliminate the
pathogenic proteins once they form aggre-
gates? The main reason is that an increase in
autophagosomes is not always indicative of an
increase in autophagy—at least, not of more
degradation through autophagy. Cells could
contain more autophagosomes when macro-
autophagy is upregulated (more formation
of autophagosomes) but also when clearance
of autophagosomes is impaired (less fusion
with and degradation of autophagosomes by
lysosomes)21,32. Understanding the nature
of the changes in the autophagic pathway
leading to autophagic malfunction has now
become a priority.
Because autophagic degradation involves
multiple steps, we discuss the consequences
of alterations in each of the different steps of
macroautophagy in the context of different
neurodegenerative disorders (Fig. 1).
Induction of autophagy. Formation of the
isolation membrane of the autophagosome,
called the phagophore, is the earliest event
in macroautophagy. Discrete regions in the
endoplasmic reticulum (the omegasomes)
may serve as the nucleation site in mamma-
lian cells33 where components required for the formation of the iso-
lation membrane (Atg or autophagy-related proteins) are recruited.
For the most part, Atg proteins that participate in the formation of
the isolation membrane—the Atg5-Atg12-Atg16 complex, the LC3-
phosphatidylethanolamine protein-to-lipid conjugation complex and
their corresponding conjugating enzymes34—do not seem to exist
in limiting amounts inside cells. Although knockouts and knock-
downs of components such as Atg5 or Atg7 have been extensively
used to suppress macroautophagy7,8, pathological conditions arising
by depletion of these factors in mammals have yet to be identified.
However, decreases in effector Atg proteins has been reported in the
brain of aging flies, and restoration of proteins to their youthful lev-
els delays neurodegeneration and extends the flies’ lifespan35. More
limiting seems to be the class III phosphatidylinositol-3-kinase com-
plex (PI3K) that mediates the nucleation of the phagophore. Three
proteins—Vps15, Vps34 and beclin-1—are essential components of
this complex, and their recruitment to the phagophore initiates the
nucleation process36,37 (Fig. 1, panel 1). Cellular levels of beclin-1
have often been correlated with autophagic activity, and hetero-
zygous deletion of beclin-1 leads to neurodegeneration9. In contrast,
the increases in beclin-1 described in different neurodegenerative
disorders often reflect neuronal upregulation of macroautophagy in
response to pathogenic proteins or neuronal injury38. The limiting
nature of beclin-1 could be behind the aggravating effect of aging in
neurodegeneration, as lower levels of beclin-1 have been reported
in brains from old individuals39. However, cellular availability of
beclin-1, rather than just total cellular abundance, might hold the key
to defective autophagy in different pathologies. Integration of beclin-1
into the nucleation complex is negatively regulated by its binding to
Bcl-2 (ref. 40), and this itself is modulated through post-translational
modifications of beclin-1 (ref. 41). It is thus conceivable that changes
in the enzymes that mediate these post-translational modifications or
Figure 1 Possible steps of macroautophagy altered in neurodegeneration. The possible defects that
could be behind macroautophagy malfunctioning in different neurodegenerative disorders are depicted:
(1) reduced autophagy induction; (2) enhanced autophagy repression; (3) altered cargo recognition;
(4) inefficient autophagosome/lysosome fusion, and (5) inefficient degradation of the autophagic cargo
in lysosomes. Examples of neurodegenerative diseases for which alterations in each autophagic step have
been described are shown. Atg, autophagy-related proteins; Vps, vesicular protein secretion protein; GβL,
G protein beta protein subunit-like; HDAC, histone deacetylase; AD, Alzheimer’s disease; HD, Huntington’s
disease; PD, Parkinson’s disease; LSD, lysosomal storage disorders; SMA, spinal muscular atrophy.
© 2010 Nature America, Inc. All rights reserved.
nature neuroscience VOLUME 13 | NUMBER 7 | JULY 2010
in the cellular subcompartmentalization of beclin-1 could underlie
autophagic failure in some neurodegenerative settings12,37,40,41.
Macroautophagy is negatively regulated by a second major kinase
complex, the serine/threonine protein kinase mTOR (mammalian
target of rapamycin)42 (Fig. 1, panel 2). Chemical inhibition of
mTOR, often used to activate macroautophagy, was indeed the
first autophagic manipulation shown to slow the progress of neuro-
degeneration28, and sequestration of mTOR in protein aggregates
has been proposed to mediate upregulation of macroautophagy in
animal models of Huntington’s disease28. However, whether or not
changes in the autophagic targets downstream of mTOR43 occur in
neurodegeneration requires further investigation.
Cargo sequestration. Although macroautophagy was previously
considered an ‘in-bulk’ process, overwhelming evidence now
supports selectivity in the sequestration of autophagic cargo44,45
(Fig. 1, panel 3). Recognition of certain post-translational modi-
fications, often polyubiquitination, by molecules that bind both
cargo and components of the autophagic machinery mediates this
selectivity45,46. p62, the first cargo-recognizing molecule identified,
binds preferentially to a particular type of ubiquitin linkage (Lys63)
on the surface of protein aggregates and brings autophagosome for-
mation to these aggregates through its interaction with LC347,48. p62
has turned out to be a complex molecule that not only participates
in autophagic clearance of aggregates but also modulates aggregate
formation and regulates stress-response genes. These other functions
of p62 could explain in part why deletion of p62 ameliorates hepatic
injury in animals deficient for macroautophagy in liver49. This effect
is, however, organ specific, because deletion of p62 does not suppress
neurodegeneration in neuronal macroautophagy–deficient mice49.
Cargo recognition by p62 is not limited to protein aggregates but
also includes organelles and even pathogens50,51. Ubiquitin is also
the recognition signal for NBR1 and NDP52, recently identified p62-
like molecules. The targeted cargo in the case of NBR1 is limited
to proteins52, whereas NDP52 recognizes ubiquitin-coated bacteria
inside human cells53.
Inefficient recognition of aggregate proteins by macroautophagy,
which depends on the nature of the aggregate protein, has been
described in an aggregate-prone experimental setting54. For
example, whereas cytosolic inclusions of α-synuclein, synphilin-1,
mutant tau or huntingtin are readily amenable to macroautophagy
removal, inclusions of p38 and desmin persist in the cytosol even
when macroautophagy is maximally activated54. Unexpectedly,
p62 is present in both types of aggregates, suggesting that p62
is necessary but not sufficient to bring together the autophagy
machinery and activate autophagic clearance. Intrinsic proper-
ties of the aggregating proteins, specific post-translational modi-
fications or changes in their interaction with cargo-recognizing
molecules could determine amenability to autophagic clearance. In
this respect, acetylation has recently shown to modulate autophagic
clearance, although with different effect, depending on the sub-
strate protein. Thus, whereas acetylation of a fragment of hunting-
tin facilitates its autophagic clearance55, acetylation of ataxin-7
prevents its autophagy-mediated turnover56.
Changes not only in the substrates but also in the autophagic system
itself could lead to inefficient cargo recognition. In fact, a paradoxical
decrease in macroautophagy-mediated degradation, despite proper for-
mation and clearance of autophagosomes, has recently been identified in
different Huntington’s disease models57. Analysis of these autophagosomes
reveals a marked decrease in their cargo content, giving the impression
of ‘empty’ autophagosomes. Because the failure to recognize cargo is not
limited to a particular cytosolic component, it is plausible that a primary
defect in the autophagosome membrane is behind the observed failure.
Autophagosome clearance. Degradation of the sequestered cargo
only occurs when autophagosomes fuse to lytic compartments (that is,
lysosomes or endosomes). In contrast to our understanding in yeast,
where a subset of SNARE proteins has been shown to mediate fusion
of autophagosomes to the vacuole, the components that participate in
fusion of mammalian autophagosomes to lysosomes or endosomes are
poorly characterized2. So far, only the Rab7 GTPase and the SNARE
Vtilb have been shown necessary for mammalian autophagic fusion,
although the participation of other Rab proteins and several vacuolar-
associated SNARE proteins has also been proposed2. In addition to
these components in the membrane of autophagosomes and lyso-
somes, autophagosome clearance also involves the participation of
the cellular cytoskeleton and cytosolic modulators1–4.
Alterations in autophagosome clearance have become a common
theme for a growing number of neurodegenerative disorders. The
distinctive characteristic of the affected neurons is an increase in the
number of autophagic vacuoles that does not associate with increased
autophagic flux. Defects can originate from the inability to mobilize
autophagosomes from their site of formation toward lysosomal or
endosomal compartments, decreased fusion between their mem-
branes or decreased proteolysis inside lysosomes (Fig. 1, panel 4).
For example, changes in the properties of microtubules, motor-
associated proteins such as dynein, dynactin or tubulin deacetylases
such as HDAC6 have been described in different neurodegenerative
settings with altered macroautophagy58–62. Cells defective in HDAC6
also show a primary defect in vesicular fusion that is independent of
microtubules, involving instead the actin cytoskeleton63. Formation
of actin bundles at the surface of autophagosomes is required
for fusion63, but it is only needed for quality-control autophagy
and not for starvation-induced autophagy. This finding is parti-
cularly interesting because it supports the existence of mechanistic
differences in the way macroautophagy is performed in response to
In some instances, autophagosome–lysosome fusion occurs but
degradation of the delivered cargo is incomplete or nonexistent
(Fig. 1, panel 5). Changes in the lysosomal lumen, such as reduced
lysosomal acidification, accumulation of undigested by-products
and decreased content or activity of lysosomal hydrolases, have been
described behind such degradative failure. In this respect, many
conditions that fall into the category of lysosomal storage disorders—a
group of diseases characterized by deficit or malfunctioning of
specific lysosomal enzymes—have an associated deficient autophagic
clearance that could explain, at least in part, the neurological symp-
toms often associated with these disorders64–66. A primary defect in
lysosomal acidification has also been recently identified in forms of
Alzheimer’s disease resulting from alterations in presenilin-1 (ref. 67).
The lower proteolytic capability of these lysosomes leads to the mas-
sive neuronal accumulation of undegraded autophagosomes observed
in the Alzheimer’s disease–affected brain at advanced stages.
Consequences of autophagic failure
Defective autophagy has different effects in cellular homeostasis
depending on the autophagic step primarily affected. Failure to
induce autophagosome formation results in cytosolic persistence
of unsequestered cargo, which could promote aggregation of other
intracellular components (acting as an aggregation ‘seed’) or become
a source of toxic products (for example, damaged mitochondria
may produce reactive oxygen species). Accumulation of protein
© 2010 Nature America, Inc. All rights reserved.
VOLUME 13 | NUMBER 7 | JULY 2010 nature neuroscience
aggregates, higher content of abnormal,
nonfunctional mitochondria, deformities of
the endoplasmic reticulum, and an increase
in the number and size of lipid droplets have
been described in different conditional ATG
When autophagic failure originates from
inefficient cargo recognition, the extent of
cellular impairment depends on whether rec-
ognition problems are limited to a particular
type of cargo or they affect sequestration of all
intracellular components. The consequences
of general failure to recognize autophagic
cargo are the same as those when autophagy
induction fails, described above. Because
autophagosomes are still formed, however,
bulk removal of randomly sequestered solu-
ble components is often preserved57. When
only a particular type of cargo escapes tar-
geted autophagy, the cellular consequences
depend on the effects that accumulation of
that cargo can cause. For example, inability
to recognize mitochondria results in poor
mitochondrial turnover, alterations in
mitochondria dynamics and the increase in
oxidative damage associated with mito-
In circumstances when the autophagic
defect originates from poor clearance of
autophagosomes, accumulation of auto-
phagosomes inside cells can be detrimental for neurons. Although
autophagosome formation would at least prevent the undesir-
able effects of unsequestered cytosolic cargo, this expansion of the
autophagic compartment can interfere with intracellular trafficking70.
Furthermore, autophagosomes can become a source of cytotoxic
products. For example, in cellular and animal models of Alzheimer’s
disease, the presence of the amyloid precursor protein (APP) in the
accumulating autophagosomes, along with the protease complex
responsible for its cleavage into the pathogenic peptide β1-42,
converts autophagosomes into an endogenous source of this patho-
genic product70. Lastly, autophagic compartments that persist longer
than usual in the cytosol can become leaky, and if leakage occurs after
lysosomal fusion, the release of lysosomal enzymes often activates
Looking for another way out during macroautophagic failure
Current pharmacological options to modulate autophagy in vivo
by directly acting on autophagic components are still very limited.
Further expansion of the therapeutic options could be attained
through a better understanding of the compensatory mechanisms and
autophagic alternatives that are activated by cells when autophagy
fails. In recent years, it has become evident that macroautophagy
acts in a coordinated manner with other cellular proteolytic mecha-
nisms72,73. The first insights into this coordinated function were
obtained by analyzing the consequences of blocking other proteolytic
systems on macroautophagy and vice versa (Fig. 2). Cells respond
to blockage of CMA by activating macroautophagy in a constitutive
manner72. Although the two pathways are not redundant, compen-
satory activation of macroautophagy in basal conditions preserves
homeostasis in cells with compromised CMA72. Likewise, CMA is
upregulated in response to macroautophagy blockage73. Cross-talk
between these pathways is of particular interest in neurodegeneration
because primary blockage of CMA has been identified in Parkinson’s
disease models and certain tauopathies74–76. Pathogenic variants of
α-synuclein and truncated forms of tau interfere with normal func-
tioning of the CMA translocation complex, thus reducing degra-
dation of other CMA substrates (damaged and misfolded cytosolic
proteins), which accumulate in the cytosol and compromise neu-
ronal function74–76. The activation of macroautophagy observed in
Parkinson’s disease24 may be secondary to CMA blockage and could
help alleviate these conditions.
Also of increasing interest are the connections between macro-
autophagy and other, nonautophagic lysosomal pathways such as
endocytosis (Fig. 2). Disrupted formation of multivesicular bodies
due to ESCRT-III dysfunction in the membrane of late endosomes
leads to reduced autophagic flux and autophagosome accumu-
lation in models of frontotemporal dementia77,78. Additional
genetic studies have revealed that other components essential
for endosome biogenesis (namely, ESCRT-I and ESCRT-II, their
regulatory ATPase Vps4 and the endosomal kinase Fab1) are all
required for autophagy78. Disruption of these endosomal proteins
leads to accumulation of cytosolic polyubiquitinated pathogenic
proteins such as huntingtin or TDP-43 (a component of protein
inclusions seen in ALS), as expected from autophagic failure79,80.
Functional endosomes are important for autophagosome clearance,
likely through the fusion between the two compartments to form
amphisomes. Amphisomes are hybrid vesicular compartments that
arise from the fusion of autophagosomes with endosomes instead
of with lysosomes. Enhanced formation of amphisomes has been
demonstrated when autophagosome–lysosome fusion is compro-
mised81, which in turn accommodates augmented formation of
autophagosomes82 (Fig. 2).
Figure 2 Cross-talk among macroautophagy and different cellular proteolytic systems. The
consequences of macroautophagic blockage on the activity of other autophagic pathways, on
endocytosis and on the ubiquitin proteasome system (UPS) and the consequences of changes in these
pathways on macroautophagy are depicted. Examples of neurodegenerative disorders for which this
cross-talk has been shown to be relevant are indicated in the red boxes and are discussed in more
detail in the text. MVB, multivesicular bodies; CMA, chaperone-mediated autophagy; UPS, ubiquitin
proteasome system; AD, Alzheimer’s disease; HD, Huntington’s disease; PD, Parkinson’s disease; FTD,
frontotemporal dementia; ALS, amyotrophic lateral sclerosis; SMA, spinal muscular atrophy.
© 2010 Nature America, Inc. All rights reserved.
nature neuroscience VOLUME 13 | NUMBER 7 | JULY 2010
These interactions between the autophagic and endocytic pathways
could be especially important in the case of prion diseases because
endocytosis is a principal route of cellular entry for pathogenic forms
of prion proteins (PrPsc)83. Furthermore, endocytic compartments,
specifically multivesicular bodies, can also mediate transmission of
the pathogenic protein between cells. Upon fusion of endosomes and
plasma membrane, the PrPsc located in the luminal vesicles of multi-
vesicular bodies gains access to the extracellular medium in the form
of exosomes83. Similar interactions with the endocytic system have
been proposed for other pathogenic proteins, such as amyloid-β,
α-synuclein and tau proteins, involved in noninfectious neuro-
degenerative disorders84. In theory, conditions that favor endosomal
degradation over endosomal recycling should facilitate elimination
of the pathogenic proteins by the lysosomal system. In this scenario,
enhanced fusion of autophagosomes with endosomes may reroute
the endosomal compartments toward lysosomes. Further investiga-
tion is necessary to determine whether or not this is the mecha-
nism behind the lower intracellular levels of PrPsc and reduced PrPsc
propagation observed upon upregulation of macroautophagy with
trehalose and lithium85.
The cellular connections of macroautophagy extend beyond the
lysosomal system to other proteolytic systems. Special attention has
been paid to the interplay between macroautophagy and the ubiquitin
proteasome system (UPS) (Fig. 2) (reviewed in ref. 86). Cells respond
to acute proteasome blockage by upregulating macroautophagy27,87,
whereas persistent chronic blockage of this protease leads to consti-
tutively upregulated macroautophagy but failure to further activate
macroautophagy in response to stress88. Chemical upregulation of
macroautophagy in mice protects them from the neurodegeneration
induced upon inhibition of proteasomes89, reinforcing the possible
therapeutic implications of this cross-talk. The massive accumula-
tion of polyubiquitinated aggregates resulting from genetic block-
age of macroautophagy7,8 indicates that polyubiquitinated proteins,
initially considered exclusive cargo of the UPS, are also substrates of
the autophagic system. However, it remains controversial whether
macroautophagy only engulfs these proteins when they are in aggre-
gates or also degrades soluble polyubiquitinated proteins in a selective
manner. Differences in the types of ubiquitin linkage may determine
delivery to one or another degradative pathway; whereas ubiquitina-
tion of Lys48 leads preferentially to UPS degradation, there is growing
evidence that Lys63-ubiquitinated proteins may be rerouted to macro-
autophagy for degradation48,90. A promising possible modulator of the
macroautophagy and UPS is p53, a well-characterized UPS substrate
that has recently been shown to upregulate macroautophagy91. Failure
to degrade p53 by the UPS will increase its cytosolic levels, leading to
activation of macroautophagy. In return, increased autophagy should
facilitate p53 clearance and prevent engagement of the mitochondrial
apoptotic pathways downstream of p53 (ref. 91). The microtubule-
associated deacetylase HDAC6 also links polyubiquitinated proteins
and autophagy, as it has been shown to be essential for rescue of the
degeneration associated with proteasome failure in an autophagy-
dependent manner87. In contrast, blockage of macroautophagy does
not enhance UPS activity but instead compromises its function92. This
effect seems mediated by p62, a putative substrate of both systems93
that, when it accumulates in the cytosol owing to impaired macro-
autophagy, competes with other ubiquitinated proteins for delivery
to the proteasome92 (Fig. 2).
Connections between macroautophagy and the UPS are not
limited to the removal of cytosolic ubiquitinated proteins but also
involve removal of organelles. For example, ubiquitination of con-
stituent proteins in the membranes of peroxisomes mediates their
macroautophagy51. This new connection between ubiquitination and
organelle autophagy may be particularly important in Parkinson’s
disease–affected neurons. In fact, two genes related to familial forms
of Parkinson’s disease, the ubiquitin ligase parkin and the serine/
threonine kinase PINK1, have recently been implicated in autophagy
of dysfunctional mitochondria68. PINK1 accumulates selectively on
dysfunctional mitochondria and induces translocation of parkin
to the depolarized mitochondria. Subsequently, parkin-mediated
ubiquitination of mitochondrial proteins by Lys63 and Lys27 link-
age favors mitochondrial aggregation and recruitment of p62, which
brings along the autophagic machinery69. Mutant forms of these pro-
teins disrupt mitophagy at different steps—translocation, aggregation,
ubiquitination and autophagic clearance68,94.
Therapeutic considerations for each autophagic failure type
Identification of the specific autophagic step(s) affected in the differ-
ent neuronal pathologies is an important consideration for the future
development of therapeutic interventions that depend on modulat-
ing autophagy to prevent neuronal degeneration. The nature of the
autophagic defect, the cellular response to that defect and elapsed time
into the progression of the disease should all be taken into account
during the implementation of these therapeutic approaches.
Conditions resulting from hampered macroautophagy induction
should benefit from treatments that activate macroautophagy. In
contrast, inhibition of autophagy should be remedial when exces-
sive activation of autophagy leads to cytosolic depletion of essential
organelles95. Autophagy activators may have a limited beneficial effect
in neurodegenerative disorders arising from defective cargo recogni-
tion. In fact, activation of autophagosome formation may increase
the amount of cargo randomly sequestered and degraded through
macroautophagy, but the loss of selectivity in recognizing the cargo
is likely to decrease the efficiency of the process. A better charac-
terization of cargo-recognition molecules is necessary for the design
of molecular interventions aimed at enhancing cargo recognition.
Activation of autophagy can become detrimental in the context of the
massive accumulation of undegraded autophagic vacuoles observed
in many neurodegenerative diseases. In fact, treatments that inhibit
autophagosome formation have been shown to improve neuronal
viability, at least temporarily, in conditions such as frontotemporal
dementia, ischemic injury or Alzheimer’s disease, where most of the
autophagosome accumulation originates from problems in clear-
ance21,77. The optimal treatment should enhance autophagosome
clearance by the lysosomal compartment. Although pharmacological
compounds with these effects are as yet unavailable, remarkably good
results have been observed with promoting lysosomal biogenesis by
overexpression of the transcription factor EB96. The new and healthy
lysosomes may mediate removal of the accumulated autophagosomes,
although it remains unclear for how long and to what extent extra
formation of lysosomes can be maintained.
Lastly, an aspect that could offer considerable room for therapeutic
manipulation in the future is the increasing number of autophagic
variations that coexist in a given cell (Fig. 3). It has become evident
that different mechanisms can lead to formation of autophagosomes,
whereas some molecular components once thought to be essen-
tial for macroautophagy can be dispensable. As a case in point, we
now know that there is mTOR-dependent and mTOR-independent
autophagy46,97,98, noncanonical autophagy that occurs even in the
absence of beclin-1 (ref. 99) and autophagosome formation even in
the absence of Atg5 and Atg7 (ref. 100) (Fig. 3). An important task in
the coming years will be matching these different autophagic variants
with the different conditions that result in autophagic activation.
© 2010 Nature America, Inc. All rights reserved.
VOLUME 13 | NUMBER 7 | JULY 2010 nature neuroscience
The traditional division into basal and starvation-induced macro-
autophagy has been revised to make room for other cellular events
requiring autophagic involvement (Fig. 3). Basal in-bulk macro-
autophagy and starvation-induced autophagy still remain at the
extremes of this scale, whereas quality-control autophagy and
autophagy induced by protein aggregates, organelle stress or patho-
gen invasion are finding their locations in this classification as their
unique properties are becoming apparent. Using alternative macro-
autophagy variants to compensate for the defective ones could be an
exciting therapeutic alternative still unexplored.
We thank the numerous colleagues in the field of autophagy who through
their animated discussions have helped shape this review and S. Kaushik and
S. Orenstein for critically reading the manuscript. Work in our laboratory is
supported by US National Institutes of Health grants from the National Institute on
Aging (AG021904, AG031782), the National Institute of Diabetes and Digestive and
Kidney Diseases (DK041918), the National Institute of Neurological Disorders and
Stroke (NS038370), a Glenn Foundation Award and a Hirsch/Weill-Caulier Career
Scientist Award. E.W. is supported by a Hereditary Disease Foundation Fellowship.
ComPetIng FInAnCIAl InteRests
The authors declare no competing financial interests.
Published online at http://www.nature.com/natureneuroscience/.
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Types of macroautophagy: molecular mechanisms
Specific activation of a type of
macroautophagy to compensate for another?
Figure 3 Variations of the macroautophagic process. Types of macroautophagy
depending on the stimuli that mediate their activation (top) or on the
molecular mechanisms involved in autophagy activation and execution
(bottom). As new understanding of these different autophagy variants is
gained, it is possible that activation of one autophagic variant could be used
to compensate for defects in other autophagy variant. Ctr, control.
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