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Parkinson's disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes alpha-Synuclein externalization via exosomes

Abstract

alpha-Synuclein plays a central causative role in Parkinson's disease (PD). Increased expression of the P-type ATPase ion pump PARK9/ATP13A2 suppresses alpha-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 alpha-Synuclein. Elevated ATP13A2 expression reduced intracellular alpha-Synuclein levels and increased alpha-Synuclein externalization in exosomes >3-fold whereas ATP13A2 knockdown decreased alpha-Synuclein externalization. An increased export of exosome-associated alpha-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 alpha-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.

Type Journal
ISBN 1460-2083 (Electronic) 0964-6906 (Linking)
Authors Kong, S. M.; Chan, B. K.; Park, J. S.; Hill, K. J.; Aitken, J. B.; Cottle, L.; Farghaian, H.; Cole, A. R.; Lay, P. A.; Sue, C. M.; Cooper, A. A.;
Garvan Authors A/Prof Antony Cooper , Kathryn Hill , Louise Cottle
Publisher Name HUMAN MOLECULAR GENETICS
Published Date 2014-01-01 00:00:00
Published Volume 23
Published Issue 11
Published Pages 2816-33
URL http://www.ncbi.nlm.nih.gov/pubmed/24603074
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?12367_12746/Hum. Mol. Genet.-2014-Kong-2816-33.pdf