title: Deficiency of ATP13A2 leads to lysosomal dysfunction, α-synuclein accumulation, and neurotoxicity.
abstract: 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.affiliation: Department of Neurology, Harvard Medical School, Boston, MA, USA
authors.forename: Marija
authors.initials: M
authors.lastname: Usenovic
authors.forename: Emilie
authors.initials: E
authors.lastname: Tresse
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Mazzulli
authors.forename: J Paul
authors.initials: JP
authors.lastname: Taylor
authors.forename: Dimitri
authors.initials: D
authors.lastname: Krainc
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003704:Dementia / Q000473:pathology; D004622:Embryo, Mammalian; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007930:Leucine / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000473:pathology; D006180:Proton-Translocating ATPases / Q000172:deficiency* / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018709:Statistics, Nonparametric; D013997:Time Factors; D014162:Transfection; D014316:Tritium / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: C514983:ATP13A2 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D016900:Neurofilament Proteins; D034741:RNA, Small Interfering; D051844:alpha-Synuclein; C485184:enhanced green fluorescent protein; D014316:Tritium; D049452:Green Fluorescent Proteins; D004815:Epidermal Growth Factor; D007770:L-Lactate Dehydrogenase; C512478:EGFR protein, human; D066246:ErbB Receptors; D006180:Proton-Translocating ATPases; D007930:Leucine