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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.

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  • Publisher Full Text

    • Authors

    Usenovic M, Tresse E, Mazzulli JR, Taylor JP, Krainc D

    Institution

    Department of Neurology, Harvard Medical School, Boston, MA, USA

    Source

    The Journal of neuroscience : the official journal of the Society for Neuroscience 32:12 2012 Mar 21 pg 4240-6

    MeSH

    Animals
    Cells, Cultured
    Cerebral Cortex
    Dementia
    Embryo, Mammalian
    Epidermal Growth Factor
    Fibroblasts
    Gene Expression Regulation
    Green Fluorescent Proteins
    Humans
    L-Lactate Dehydrogenase
    Leucine
    Lysosomal-Associated Membrane Protein 1
    Lysosomes
    Male
    Mice
    Mice, Inbred C57BL
    Microtubule-Associated Proteins
    Mutation
    Neurofilament Proteins
    Neurons
    Parkinsonian Disorders
    Proton-Translocating ATPases
    RNA, Small Interfering
    Receptor, Epidermal Growth Factor
    Statistics, Nonparametric
    Time Factors
    Transfection
    Tritium
    alpha-Synuclein

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    22442086