Extracellular ATP induces intracellular alpha-synuclein accumulation via P2X1 receptor-mediated lysosomal dysfunction

Ming Gan, Simon Moussaud, Peizhou Jiang, Pamela J. McLean

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

The pathologic hallmark of Parkinson's disease (PD) is the accumulation of alpha-synuclein (αsyn) in susceptible neurons in the form of Lewy bodies and Lewy neurites. The etiology of PD remains unclear. Because brain injury has been suggested to facilitate αsyn aggregation, we investigated whether cellular breakdown products from damaged cells can act on neighboring healthy cells and cause intracellular αsyn accumulation and/or aggregation. Using 2 neuronal cell models, we found that extracellular adenosine triphosphate (ATP) induced a significant increase in intracellular αsyn levels between 24 and 48hours after treatment. Further investigation revealed that the observed αsyn accumulation is a result of lysosome dysfunction caused by extracellular ATP-induced elevation of lysosomal pH. Interestingly, P2X1 receptor appears to mediate the cells' response to extracellular ATP. Although Ca2+ influx via P2X1 receptor is necessary for αsyn accumulation, Ca2+ influx per se is not sufficient for increased αsyn accumulation. These findings provide new insight into our knowledge of the role of P2X receptors in PD pathogenesis and may be helpful in identifying new therapeutic targets for PD.

Original languageEnglish (US)
Pages (from-to)1209-1220
Number of pages12
JournalNeurobiology of aging
Volume36
Issue number2
DOIs
StatePublished - Feb 1 2015

Keywords

  • ATP
  • Alpha-synuclein
  • Luhmes cells
  • P2X1 receptor
  • Parkinson's disease
  • Purinergic signaling

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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