PMID- 24603074
OWN - NLM
STAT- MEDLINE
DCOM- 20150112
LR  - 20220309
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Linking)
VI  - 23
IP  - 11
DP  - 2014 Jun 1
TI  - Parkinson's disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and 
      promotes alpha-Synuclein externalization via exosomes.
PG  - 2816-33
LID - 10.1093/hmg/ddu099 [doi]
AB  - 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.
FAU - Kong, Stephanie M Y
AU  - Kong SM
AD  - Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, 
      New South Wales 2010, Australia.
FAU - Chan, Brian K K
AU  - Chan BK
FAU - Park, Jin-Sung
AU  - Park JS
FAU - Hill, Kathryn J
AU  - Hill KJ
FAU - Aitken, Jade B
AU  - Aitken JB
FAU - Cottle, Louise
AU  - Cottle L
FAU - Farghaian, Hovik
AU  - Farghaian H
FAU - Cole, Adam R
AU  - Cole AR
FAU - Lay, Peter A
AU  - Lay PA
FAU - Sue, Carolyn M
AU  - Sue CM
FAU - Cooper, Antony A
AU  - Cooper AA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140306
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (ATP13A2 protein, human)
RN  - 0 (alpha-Synuclein)
RN  - EC 3.6.3.14 (Proton-Translocating ATPases)
RN  - J41CSQ7QDS (Zinc)
SB  - IM
MH  - Autophagy
MH  - Exosomes/genetics/*metabolism
MH  - Homeostasis
MH  - Humans
MH  - Neurons/enzymology/metabolism
MH  - Parkinson Disease/*enzymology/genetics/metabolism
MH  - Proton-Translocating ATPases/genetics/*metabolism
MH  - Zinc/*metabolism
MH  - alpha-Synuclein/genetics/*metabolism
EDAT- 2014/03/08 06:00
MHDA- 2015/01/13 06:00
CRDT- 2014/03/08 06:00
PHST- 2014/03/08 06:00 [entrez]
PHST- 2014/03/08 06:00 [pubmed]
PHST- 2015/01/13 06:00 [medline]
AID - ddu099 [pii]
AID - 10.1093/hmg/ddu099 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2014 Jun 1;23(11):2816-33. doi: 10.1093/hmg/ddu099. Epub 2014 Mar 
      6.