title: Parkinson's disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes α-Synuclein externalization via exosomes.
abstract: α-Synuclein plays a central causative role in Parkinson's disease (PD). Increased expression of the P-type ATPase ion pump PARK9/ATP13A2 suppresses α-Synuclein toxicity in primary neurons. Our data indicate that ATP13A2 encodes a zinc pump; neurospheres from a compound heterozygous ATP13A2(-/-) patient and ATP13A2 knockdown cells are sensitive to zinc, whereas ATP13A2 over-expression in primary neurons confers zinc resistance. Reduced ATP13A2 expression significantly decreased vesicular zinc levels, indicating ATP13A2 facilitates transport of zinc into membrane-bound compartments or vesicles. Endogenous ATP13A2 localized to multi-vesicular bodies (MVBs), a late endosomal compartment located at the convergence point of the endosomal and autophagic pathways. Dysfunction in MVBs can cause a range of detrimental effects including lysosomal dysfunction and impaired delivery of endocytosed proteins/autophagy cargo to the lysosome, both of which have been observed in cells with reduced ATP13A2 function. MVBs also serve as the source of intra-luminal nanovesicles released extracellularly as exosomes that can contain a range of cargoes including α-Synuclein. Elevated ATP13A2 expression reduced intracellular α-Synuclein levels and increased α-Synuclein externalization in exosomes >3-fold whereas ATP13A2 knockdown decreased α-Synuclein externalization. An increased export of exosome-associated α-Synuclein may explain why surviving neurons of the substantia nigra pars compacta in sporadic PD patients were observed to over-express ATP13A2. We propose ATP13A2's modulation of zinc levels in MVBs can regulate the biogenesis of exosomes capable of containing α-Synuclein. Our data indicate that ATP13A2 is the first PD-associated gene involved in exosome biogenesis and indicates a potential neuroprotective role of exosomes in PD.
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
authors.forename: Stephanie M Y
authors.initials: SM
authors.lastname: Kong
authors.forename: Brian K K
authors.initials: BK
authors.lastname: Chan
authors.forename: Jin-Sung
authors.initials: JS
authors.lastname: Park
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Hill
authors.forename: Jade B
authors.initials: JB
authors.lastname: Aitken
authors.forename: Louise
authors.initials: L
authors.lastname: Cottle
authors.forename: Hovik
authors.initials: H
authors.lastname: Farghaian
authors.forename: Adam R
authors.initials: AR
authors.lastname: Cole
authors.forename: Peter A
authors.initials: PA
authors.lastname: Lay
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Sue
authors.forename: Antony A
authors.initials: AA
authors.lastname: Cooper
mesh_terms: D001343:Autophagy; D055354:Exosomes / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D009474:Neurons / Q000201:enzymology / Q000378:metabolism; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D006180:Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: C514983:ATP13A2 protein, human; D051844:alpha-Synuclein; D006180:Proton-Translocating ATPases; D015032:Zinc