PINK1 defect causes mitochondrial dysfunction, proteasomal deficit and alpha-synuclein aggregation in cell culture models of Parkinson's disease

PLoS One. 2009;4(2):e4597. doi: 10.1371/journal.pone.0004597. Epub 2009 Feb 26.

Abstract

Mutations in PTEN induced kinase 1 (PINK1), a mitochondrial Ser/Thr kinase, cause an autosomal recessive form of Parkinson's disease (PD), PARK6. Here, we report that PINK1 exists as a dimer in mitochondrial protein complexes that co-migrate with respiratory chain complexes in sucrose gradients. PARK6 related mutations do not affect this dimerization and its associated complexes. Using in vitro cell culture systems, we found that mutant PINK1 or PINK1 knock-down caused deficits in mitochondrial respiration and ATP synthesis. Furthermore, proteasome function is impaired with a loss of PINK1. Importantly, these deficits are accompanied by increased alpha-synclein aggregation. Our results indicate that it will be important to delineate the relationship between mitochondrial functional deficits, proteasome dysfunction and alpha-synclein aggregation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Humans
  • Mitochondria / pathology*
  • Mitochondrial Proteins / metabolism
  • Models, Biological
  • Mutation
  • Oxidative Phosphorylation
  • Parkinson Disease
  • Proteasome Endopeptidase Complex / deficiency*
  • Protein Kinases / genetics*
  • alpha-Synuclein / metabolism*

Substances

  • Mitochondrial Proteins
  • alpha-Synuclein
  • Protein Kinases
  • PTEN-induced putative kinase
  • Proteasome Endopeptidase Complex