Parkinson's disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes alpha-Synuclein externalization via exosomes
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.
|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.;|
|Publisher Name||HUMAN MOLECULAR GENETICS|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/24603074|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/12367|