|Deficiency of ATP13A2 leads to lysosomal dysfunction, α-synuclein accumulation, and neurotoxicity.|
|PMID: 22442086 Owner: NLM Status: MEDLINE|
|The autophagy-lysosomal pathway plays an important role in the clearance of long-lived proteins and dysfunctional organelles. Lysosomal dysfunction has been implicated in several neurodegenerative disorders including Parkinson's disease and related synucleinopathies that are characterized by accumulations of α-synuclein in Lewy bodies. Recent identification of mutations in genes linked to lysosomal function and neurodegeneration has offered a unique opportunity to directly examine the role of lysosomes in disease pathogenesis. Mutations in lysosomal membrane protein ATP13A2 (PARK9) cause familial Kufor-Rakeb syndrome characterized by early-onset parkinsonism, pyramidal degeneration and dementia. While previous data suggested a role of ATP13A2 in α-synuclein misfolding and toxicity, the mechanistic link has not been established. Here we report that loss of ATP13A2 in human fibroblasts from patients with Kufor-Rakeb syndrome or in mouse primary neurons leads to impaired lysosomal degradation capacity. This lysosomal dysfunction results in accumulation of α-synuclein and toxicity in primary cortical neurons. Importantly, silencing of endogenous α-synuclein attenuated the toxicity in ATP13A2-depleted neurons, suggesting that loss of ATP13A2 mediates neurotoxicity at least in part via the accumulation of α-synuclein. Our findings implicate lysosomal dysfunction in the pathogenesis of Kufor-Rakeb syndrome and suggest that upregulation of lysosomal function and downregulation of α-synuclein represent important therapeutic strategies for this disorder.|
|Marija Usenovic; Emilie Tresse; Joseph R Mazzulli; J Paul Taylor; Dimitri Krainc|
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|Type: Journal Article; Research Support, N.I.H., Extramural|
|Title: The Journal of neuroscience : the official journal of the Society for Neuroscience Volume: 32 ISSN: 1529-2401 ISO Abbreviation: J. Neurosci. Publication Date: 2012 Mar|
|Created Date: 2012-03-23 Completed Date: 2012-05-18 Revised Date: 2013-06-26|
Medline Journal Info:
|Nlm Unique ID: 8102140 Medline TA: J Neurosci Country: United States|
|Languages: eng Pagination: 4240-6 Citation Subset: IM|
|Department of Neurology, Harvard Medical School, Boston, MA, USA|
|APA/MLA Format Download EndNote Download BibTex|
Cerebral Cortex / cytology
Dementia / pathology
Epidermal Growth Factor / metabolism
Fibroblasts / metabolism
Gene Expression Regulation / genetics*
Green Fluorescent Proteins / genetics
L-Lactate Dehydrogenase / metabolism
Leucine / metabolism
Lysosomal-Associated Membrane Protein 1 / metabolism
Lysosomes / metabolism*, pathology
Mice, Inbred C57BL
Microtubule-Associated Proteins / metabolism
Mutation / genetics
Neurofilament Proteins / metabolism
Neurons / drug effects, metabolism*
Parkinsonian Disorders / pathology
Proton-Translocating ATPases / deficiency*, genetics
RNA, Small Interfering / genetics, metabolism
Receptor, Epidermal Growth Factor / metabolism
Tritium / metabolism
alpha-Synuclein / metabolism*
|R01 NS051303-04/NS/NINDS NIH HHS; R01 NS070168-03/NS/NINDS NIH HHS; R01 NS076054-01/NS/NINDS NIH HHS; R01AG031587/AG/NIA NIH HHS; R01NS051303/NS/NINDS NIH HHS|
|0/Lysosomal-Associated Membrane Protein 1; 0/Microtubule-Associated Proteins; 0/Neurofilament Proteins; 0/RNA, Small Interfering; 0/alpha-Synuclein; 0/enhanced green fluorescent protein; 0/light chain 3, human; 10028-17-8/Tritium; 147336-22-9/Green Fluorescent Proteins; 61-90-5/Leucine; 62229-50-9/Epidermal Growth Factor; EC 18.104.22.168/L-Lactate Dehydrogenase; EC 22.214.171.124/EGFR protein, human; EC 126.96.36.199/Receptor, Epidermal Growth Factor; EC 188.8.131.52/ATP13A2 protein, human; EC 184.108.40.206/Proton-Translocating ATPases|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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