Document Detail


Deficiency of ATP13A2 leads to lysosomal dysfunction, α-synuclein accumulation, and neurotoxicity.
MedLine Citation:
PMID:  22442086     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Marija Usenovic; Emilie Tresse; Joseph R Mazzulli; J Paul Taylor; Dimitri Krainc
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
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 
Date Detail:
Created Date:  2012-03-23     Completed Date:  2012-05-18     Revised Date:  2014-09-21    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4240-6     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cells, Cultured
Cerebral Cortex / cytology
Dementia / pathology
Embryo, Mammalian
Epidermal Growth Factor / metabolism
Fibroblasts / metabolism
Gene Expression Regulation / genetics*
Green Fluorescent Proteins / genetics
Humans
L-Lactate Dehydrogenase / metabolism
Leucine / metabolism
Lysosomal-Associated Membrane Protein 1 / metabolism
Lysosomes / metabolism*,  pathology
Male
Mice
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
Statistics, Nonparametric
Time Factors
Transfection
Tritium / metabolism
alpha-Synuclein / metabolism*
Grant Support
ID/Acronym/Agency:
R01 NS051303/NS/NINDS NIH HHS; R01 NS051303-04/NS/NINDS NIH HHS; R01 NS070168/NS/NINDS NIH HHS; R01 NS070168-03/NS/NINDS NIH HHS; R01 NS076054/NS/NINDS NIH HHS; R01 NS076054-01/NS/NINDS NIH HHS; R01AG031587/AG/NIA NIH HHS; R01NS051303/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
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; 62229-50-9/Epidermal Growth Factor; EC 1.1.1.27/L-Lactate Dehydrogenase; EC 2.7.10.1/EGFR protein, human; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 3.6.3.14/ATP13A2 protein, human; EC 3.6.3.14/Proton-Translocating ATPases; GMW67QNF9C/Leucine
Comments/Corrections

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