AF-6 is a positive modulator of the PINK1/parkin pathway and is deficient in Parkinson's disease

Hum Mol Genet. 2013 May 15;22(10):2083-96. doi: 10.1093/hmg/ddt058. Epub 2013 Feb 7.

Abstract

Parkin E3 ubiquitin-ligase activity and its role in mitochondria homeostasis are thought to play a role in Parkinson's disease (PD). We now report that AF-6 is a novel parkin interacting protein that modulates parkin ubiquitin-ligase activity and mitochondrial roles. Parkin interacts with the AF-6 PDZ region through its C-terminus. This leads to ubiquitination of cytosolic AF-6 and its degradation by the proteasome. On the other hand, endogenous AF-6 robustly increases parkin translocation and ubiquitin-ligase activity at the mitochondria. Mitochondrial AF-6 is not a parkin substrate, but rather co-localizes with parkin and enhances mitochondria degradation through PINK1/parkin-mediated mitophagy. On the other hand, several parkin and PINK1 juvenile disease-mutants are insensitive to AF-6 effects. AF-6 is present in Lewy bodies and its soluble levels are strikingly decreased in the caudate/putamen and substantia nigra of sporadic PD patients, suggesting that decreased AF-6 levels may contribute to the accumulation of dysfunctional mitochondria in the disease. The identification of AF-6 as a positive modulator of parkin translocation to the mitochondria sheds light on the mechanisms involved in PD and underscores AF-6 as a novel target for future therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caudate Nucleus / metabolism
  • Caudate Nucleus / pathology
  • HEK293 Cells
  • Humans
  • Kinesin / genetics
  • Kinesin / metabolism*
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Mutation*
  • Myosins / genetics
  • Myosins / metabolism*
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Protein Transport / genetics
  • Proteolysis
  • Substantia Nigra / metabolism
  • Substantia Nigra / pathology
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination / genetics

Substances

  • AFDN protein, human
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein Kinases
  • PTEN-induced putative kinase
  • Myosins
  • Kinesin