ATP13A2/PARK9 regulates secretion of exosomes and α-Synuclein

Taiji Tsunemi, Kana Hamada, Dimitri Krainc*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

142 Scopus citations


Kufor–Rakeb syndrome (KRS) is caused by loss-of-function mutations in ATP13A2 (PARK9) and characterized by juvenile-onset parkinsonism,pyramidal signs, and cognitive decline. Previous studies suggested that PARK9 deficiency causes lysosomal dysfunction andα-synuclein (α-syn) accumulation, whereas PARK9 overexpression suppresses toxicity of α-syn. However, the precise mechanism ofPARK9 effect on lysosomes andα-syn has been unknown. Here, we found that overexpressed PARK9 localized to multivesicular bodies(MVBs) in the human H4 cell line. The results from patient fibroblasts showed that loss of PARK9 function leads to decreased number ofthe intraluminal vesicles in MVBs and diminished release of exosomes into culture media. By contrast, overexpression of PARK9 resultsin increased release of exosomes inH4cells and mouse primary cortical neurons. Moreover, loss ofPARK9function resulted in decreasedsecretion of α-syn into extracellular space, whereas overexpressed PARK9 promotes secretion of α-syn, at least in part via exosomes.Finally, we found thatPARK9regulates exosome biogenesis through functional interaction with the endosomal sorting complex requiredfor transport machinery. Together, these data suggest the involvement of PARK9 in the biogenesis of exosomes andα-syn secretion andraise a possibility that disruption of these pathways in patients with KRS contributes to the disease pathogenesis.

Original languageEnglish (US)
Pages (from-to)15281-15287
Number of pages7
JournalJournal of Neuroscience
Issue number46
StatePublished - Nov 12 2014


  • ATP13A2
  • Exosome
  • Multivesicular body
  • PARK9
  • Parkinson’s disease
  • α-synuclein

ASJC Scopus subject areas

  • General Neuroscience


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