Deficiency of ATP13A2 leads to lysosomal dysfunction, α-synuclein accumulation, and neurotoxicity

Marija Usenovic, Emilie Tresse, Joseph R. Mazzulli, J. Paul Taylor, Dimitri Krainc*

*Corresponding author for this work

Research output: Contribution to journalArticle

147 Citations (Scopus)

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 synucleinopa-thies that are characterized by accumulations of a-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.

Original languageEnglish (US)
Pages (from-to)4240-4246
Number of pages7
JournalJournal of Neuroscience
Volume32
Issue number12
DOIs
StatePublished - Mar 21 2012

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Synucleins
Neurons
Lysosome-Associated Membrane Glycoproteins
Lewy Bodies
Mutation
Autophagy
Parkinsonian Disorders
Lysosomes
Neurodegenerative Diseases
Organelles
Parkinson Disease
Dementia
Up-Regulation
Down-Regulation
Fibroblasts

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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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 synucleinopa-thies that are characterized by accumulations of a-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.",
author = "Marija Usenovic and Emilie Tresse and Mazzulli, {Joseph R.} and Taylor, {J. Paul} and Dimitri Krainc",
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Deficiency of ATP13A2 leads to lysosomal dysfunction, α-synuclein accumulation, and neurotoxicity. / Usenovic, Marija; Tresse, Emilie; Mazzulli, Joseph R.; Taylor, J. Paul; Krainc, Dimitri.

In: Journal of Neuroscience, Vol. 32, No. 12, 21.03.2012, p. 4240-4246.

Research output: Contribution to journalArticle

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T1 - Deficiency of ATP13A2 leads to lysosomal dysfunction, α-synuclein accumulation, and neurotoxicity

AU - Usenovic, Marija

AU - Tresse, Emilie

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