Mess with their waste disposal, and neurons clog with unwanted proteins—including those that contribute to neurodegeneration. This story line is reinforced by two new studies that strengthen the link between lysosomal dysfunction and Parkinson’s disease. Reporting in the May 30 Journal of Neuroscience, researchers led by Zhenyu Yue at Mount Sinai School of Medicine, New York, generated mice with disrupted autophagy—cellular degradation via lysosomes—in dopaminergic neurons. The animals developed motor deficits and neurodegeneration as they aged. When the researchers blocked autophagy throughout the central nervous system (CNS), the mice developed pathological deposits containing α-synuclein and leucine-rich repeat kinase 2 (LRRK2), two proteins encoded by familial PD genes. In the May 30 Proceedings of the National Academy of Sciences USA, Erwan Bezard of the University of Bordeaux, France, and colleagues reported lysosomal defects in fibroblasts from people carrying another PD gene, ATP13A2, otherwise known as PARK9. Supplying wild-type ATP13A2 protein rescued lysosomal function in these cells. These two papers have spurred the hunt for potential PD therapeutic compounds that stimulate autophagy.

Several prior lines of evidence already tie together autophagy and PD. Autophagy helps neurons clear α-synuclein pathology (Webb et al., 2003; Spencer et al., 2009; Yu et al., 2009), and an excess of wild-type α-synuclein disrupts this disposal process in mammalian cells and PD transgenic mice (Winslow et al., 2010). Moreover, PD-related LRRK2 mutations scupper autophagy in cell models and transgenic mice (Alegre-Abarrategui et al., 2009; Ramonet et al., 2011). But can disrupted autophagy lead to PD pathogenesis?

As reported in Journal of Neuroscience, first author Lauren Friedman and colleagues pursued this question by knocking out the essential autophagy gene Atg7 in dopaminergic neurons, including those in the substantia nigra that die and give rise to motor symptoms in PD. Earlier, coauthor Masaaki Komatsu at the Tokyo Metropolitan Institute of Medical Science, Japan, had shown that knocking out Atg7 across the whole mouse brain caused PD-like inclusions and neurodegeneration in the first weeks of life (ARF related news story on Komatsu et al., 2006). In the present study, the researchers directed the Atg7 deletion specifically to dopamine (and norepinephrine) neurons by crossing the previously characterized mice, which have a floxed Atg7 transgene, to transgenic mice expressing Cre recombinase in tyrosine hydroxylase (TH)-producing cells. They verified by immunofluorescent staining for Atg7 and TH that the gene was inactivated in virtually all midbrain dopaminergic neurons. Labeling of ubiquitinated inclusions showed that autophagy went awry in these cells as well

Given that autophagy started failing in the Atg7/TH conditional knockouts by the time the animals reached 30 days of age, scientists expected to see rapid cell death. Instead, they found “delayed degeneration that was reminiscent of age-dependent, late-onset PD,” Yue told ARF. The Atg7/TH mice produced less striatal dopamine and had disfigured axons by four months of age, but did not lose dopamine neurons or show significant motor problems until nine months. Furthermore, immunofluorescence and Western blots showed α-synuclein and LRRK2 accumulating in Purkinje cell neurons of CNS-wide Atg7 knockout mice, and in Atg7-deficient mouse embryonic fibroblast cells, suggesting that malfunctioning autophagy might help set the stage for PD.

Mark Cookson of the National Institute on Aging in Bethesda, Maryland, points out that the experimental approach of knocking out an essential enzyme in vulnerable neurons does not clearly establish whether autophagy is critical for PD pathogenesis. “If you have something a cell requires to survive, and you get rid of it in a group of cells, they will inevitably die,” Cookson said. “We don’t know if that thing is pathogenically important in PD.”

Nevertheless, the new paper “is very interesting and certainly further implicates autophagy as a step involved in Parkinson's pathogenesis,” David Sulzer of Columbia University Medical Campus, New York, wrote in an e-mail to Alzforum (see full comment below). Sulzer’s group also generated autophagy-deficient conditional knockouts with Atg7 deleted in dopaminergic neurons, and reported in the April 26 Neuron that these mice have abnormal presynaptic neurotransmission (Hernandez et al., 2012).

In the PNAS paper, researchers led by corresponding author Benjamin Dehay linked autophagy and PD more directly by showing that PARK9 mutations lead to loss of lysosomal function and diminished autophagosome clearance. Dehay and colleagues showed previously that the number of lysosomes drops considerably prior to dopaminergic cell death in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD (Dehay et al., 2010). Prior to that, coauthor Alfredo Ramirez and coworkers at the University of Lubeck, Germany, reported that mutations in ATP13A2—a gene in the PARK9 locus encoding a lysosomal ATPase—were linked to autosomal recessive familial parkinsonism (see ARF related news story on Ramirez et al., 2006).

To get a better handle on ATPase’s relevance to PD, Dehay and colleagues opted to study human cells and approached the German scientists for fibroblasts from PD patients who carry ATP13A2 mutations. Immunostaining, Western blot, and electron microscopy experiments revealed that lysosomes in those fibroblasts were at the wrong pH, and had trouble processing pro-apoptotic cathepsins and clearing lysosomal substrates. The researchers recapitulated this problem in ATP13A2-deficient dopaminergic neuroblastoma cells and relieved it by overexpressing wild-type ATP13A2. Consistent with their lysosomal deficits, the ATP13A2-deficient cells were unable to clear α-synuclein as well as did control cells. Dehay’s group found less ATPase in postmortem nigral tissue from sporadic PD patients than from control patients' tissue. Furthermore, immunohistochemical experiments revealed ATP13A2 in more than 90 percent of Lewy body inclusions in the PD dopaminergic neurons.

The study “makes a connection between lysosomal dysfunction, α-synuclein accumulation, and neurodegeneration,” Dehay said. “When lysosomes don’t work, we get more cathepsins released into the cytosol, which can activate apoptosis.” Malfunctioning lysosomes also cannot clear α-synuclein properly, leaving these proteins to accumulate and form Lewy body aggregates. Recent work suggests that α-synuclein and the lysosomal enzyme glucocerebrosidase (GBA) may operate in a vicious cycle, with GBA deficiency allowing α-synuclein to accumulate and α-synuclein going back to stymie lysosomal GBA activity in Gaucher’s disease, a lysosomal storage disorder with genetic association to PD (see ARF related news story). Moreover, ATP13A2 came up in a yeast screen for modifiers of α-synuclein toxicity, and overexpressing the ATPase in worms protected them from α-synuclein-induced neurodegeneration (see ARF related news story).

Building on the idea that ATP13A2 may be neuroprotective, the new data strongly suggest that the ATPase "is important for efficient lysosomal function and protein degradation” Guy Caldwell of the University of Alabama, Tuscaloosa, wrote in an e-mail to Alzforum (see full comment below).

In follow-up, the authors of both papers are pushing toward translational studies. Dehay and colleagues are screening for molecules that stimulate degradation through the autophagic-lysosomal pathway. They plan to generate ATP13A2 knockout mice and conditional knockouts with the gene deleted in dopaminergic neurons. In addition, they are trying to identify proteins that interact with the ATPase. Toward that end, researchers at Massachusetts General Hospital, Boston, in collaboration with Caldwell, identified 43 novel ATP13A2 interactors, some of which were shown to influence α-synuclein aggregation and dopaminergic neuron loss in worms (Usenovic et al., 2012). The findings were published May 29 in Human Molecular Genetics.

For their part, Yue and colleagues have identified a component of a traditional Chinese medicine that drives up autophagic activity and reduces α-synuclein levels in cultured rodent neurons and fly models for PD. They are collaborating with a biotech company to develop this compound, Yue said. Prior research has shown that autophagy-enhancing molecules can help clear aggregated huntingtin protein (Sarkar et al., 2007), and other work suggests this strategy could also help in other neurodegenerative diseases such as Alzheimer’s (see ARF related news story).—Esther Landhuis


  1. Gitler et al. (see ARF related news story) previously demonstrated that ATP13A2/PARK9 functionally modified α-synuclein toxicity in yeast, and that its overexpression protected dopamine neurons in C. elegans from age-dependent α-synuclein degeneration. This excellent new study from Dehay and colleagues provides strong support for the hypothesis that ATP13A2/PARK9 activity is important for efficient lysosomal function and protein degradation. In the context of the growing literature on the shared cellular dysfunction underlying Gaucher's disease and Parkinson's disease (Mazzulli et al., 2011), these results extend the prospect that therapeutic interventions directed at enhancement of lysosomal-autophagy pathways represent an important target for PD research. The identification of genetic and protein modifiers of ATP13A2 activity may serve to elucidate additional mechanistic insights that can expand the potential for such therapies.


    . Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011 Jul 8;146(1):37-52. Epub 2011 Jun 23 PubMed.

    View all comments by Guy Caldwell
  2. The new paper from Zhenyu Yue is very interesting, and certainly further implicates autophagy as a step involved in Parkinson's pathogenesis. This seems to provide support for other work from Richard Youle's (Narendra et al., 2010) and Charleen Chu's (Dagda et al., 2009) labs suggesting that a deficit in mitochondrial turnover by macroautophagy might occur with the parkin and PINK mutations that can cause some cases of PD. So, a mutation that directly affects macroautophagy may model a downstream step in PD. One possibility is that mutant α-synuclein first disturbs another form of autophagy, known as chaperone-mediated autophagy, and this leads to downstream consequences for macroautophagy. Thus, the similar (although not identical) ATG7 mutant mice, which both of our labs have developed, may mostly be modeling later stages in the disease.


    . PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 2010 Jan;8(1):e1000298. PubMed.

    . Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J Biol Chem. 2009 May 15;284(20):13843-55. Epub 2009 Mar 10 PubMed.

    View all comments by David Sulzer
  3. The lysosomal acidification defect linked to cytotoxicity of mutations in the P-type ATPase ATP13A2/PARK9 in Parkinson’s disease (PD) prompts comparison to the similar mechanism operating in AD due to mutations of presenilin 1. Dehay and colleagues used nearly the same extensive battery of methods as Lee et al. (2010) to evaluate autophagy and lysosomal function in fibroblasts from PD patients and other model cell systems. While the two studies implicate different lysosomal constituents in these two diseases, they reveal pathogenic mechanisms involving defects in lysosome function that are remarkably similar and mutually validating. In both diseases, a lysosomal component needed for acidification is prematurely degraded in the endoplasmic reticulum and fails to reach the lysosome in amounts required for full function. In early onset AD caused by mutations of PS1, the V01a subunit of the proton pump vATPase is improperly chaperoned by the mutant PS1 and is degraded during its exit from the ER, similarly to the fate of mutant ATPase ATP13A2 in PD. Both molecules are large multi-pass membrane ATPases involved in H+ ion transport, although the role of ATPase ATP13A2 in lysosomal acidification is an exciting new finding.

    The Dehay study raises an intriguing set of additional questions as to whether the lysosomes in specific neuron subtypes—dopaminergic neurons, in this case—are differentially regulated, why this might be, and how it might contribute to differential neuronal vulnerability. These findings reinforce the emerging concept of the lysosome as a vital regulator of diverse cell functions and as a highly vulnerable target in a growing number of neurodegenerative disorders affecting endocytosis and autophagy—processes that are especially crucial to neuron survival.


    . Loss of P-type ATPase ATP13A2/PARK9 function induces general lysosomal deficiency and leads to Parkinson disease neurodegeneration. Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9611-6. PubMed.

    . Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell. 2010 Jun 25;141(7):1146-58. PubMed.

Make a Comment

To make a comment you must login or register.


News Citations

  1. Autophagy Prevents Inclusions, Neurodegeneration
  2. PARK9 Is Unveiled—Mutations Compromise Orphan Lysosomal ATPase
  3. Feedback Loop—Molecular Mechanism for PD, Gaucher’s Connection
  4. Yeast Screen Implicates PARK9 in Synuclein Toxicity
  5. Lysosomal Block Clogs Transport, Swells Neurites

Paper Citations

  1. . Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem. 2003 Jul 4;278(27):25009-13. PubMed.
  2. . Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson's and Lewy body diseases. J Neurosci. 2009 Oct 28;29(43):13578-88. PubMed.
  3. . Metabolic activity determines efficacy of macroautophagic clearance of pathological oligomeric alpha-synuclein. Am J Pathol. 2009 Aug;175(2):736-47. PubMed.
  4. . α-Synuclein impairs macroautophagy: implications for Parkinson's disease. J Cell Biol. 2010 Sep 20;190(6):1023-37. PubMed.
  5. . LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model. Hum Mol Genet. 2009 Nov 1;18(21):4022-34. PubMed.
  6. . Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLoS One. 2011;6(4):e18568. PubMed.
  7. . Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006 Jun 15;441(7095):880-4. PubMed.
  8. . Regulation of presynaptic neurotransmission by macroautophagy. Neuron. 2012 Apr 26;74(2):277-84. PubMed.
  9. . Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet. 2006 Oct;38(10):1184-91. PubMed.
  10. . Identification of novel ATP13A2 interactors and their role in α-synuclein misfolding and toxicity. Hum Mol Genet. 2012 Sep 1;21(17):3785-94. PubMed.
  11. . Small molecules enhance autophagy and reduce toxicity in Huntington's disease models. Nat Chem Biol. 2007 May 1;3(6):331-8.

Further Reading


  1. . Regulation of presynaptic neurotransmission by macroautophagy. Neuron. 2012 Apr 26;74(2):277-84. PubMed.
  2. . Identification of novel ATP13A2 interactors and their role in α-synuclein misfolding and toxicity. Hum Mol Genet. 2012 Sep 1;21(17):3785-94. PubMed.
  3. . Small molecules enhance autophagy and reduce toxicity in Huntington's disease models. Nat Chem Biol. 2007 May 1;3(6):331-8.
  4. . Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release. Nat Commun. 2012;3:731. PubMed.
  5. . Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nat Genet. 2009 Mar;41(3):308-15. PubMed.

Primary Papers

  1. . Loss of P-type ATPase ATP13A2/PARK9 function induces general lysosomal deficiency and leads to Parkinson disease neurodegeneration. Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9611-6. PubMed.
  2. . Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of α-synuclein and LRRK2 in the brain. J Neurosci. 2012 May 30;32(22):7585-93. PubMed.