Mitochondrial dysfunction and Parkinson disease: a Parkin-AMPK alliance in neuroprotection

Ann N Y Acad Sci. 2015 Sep:1350:37-47. doi: 10.1111/nyas.12820. Epub 2015 Jun 29.

Abstract

Although a subject of intense research, the etiology of Parkinson disease (PD) remains poorly understood. However, a wide range of studies conducted over the past few decades have collectively implicated aberrant mitochondrial homeostasis as a key contributor to the development of PD. Particularly strong support for this came from the recent demonstration that parkin, a familial PD-linked gene, is a critical regulator of mitochondrial quality control. Indeed, Parkin appears to be involved in all stages of the mitochondrial life cycle (i.e., from biogenesis to its exit from the cell (via mitophagy). Interestingly, the role of Parkin in the biogenesis and clearance of mitochondria is akin to that performed by the energy sensor AMP-activated protein kinase (AMPK), suggesting that the two proteins might act in a functionally converging manner to maintain the quality of cellular mitochondria. In this review, we discuss the contribution of mitochondrial dysfunction to PD pathogenesis and the role of Parkin and AMPK in preserving neuronal mitochondrial homeostasis. Alongside this, we will also articulate our thoughts on the potential alliance between Parkin and AMPK in offering neuroprotection through their ability to maintain energy balance in the brain.

Keywords: LRRK2; PGC-1α; PINK1; dopamine; mitophagy; neurodegeneration.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Humans
  • Mitochondria / enzymology
  • Mitochondria / metabolism*
  • Mitochondrial Diseases / etiology*
  • Mitochondrial Turnover
  • Models, Biological*
  • Mutation
  • Neurons / enzymology
  • Neurons / metabolism*
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism
  • Parkinson Disease / physiopathology*
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein Kinases
  • PTEN-induced putative kinase
  • AMP-Activated Protein Kinases
  • PRKAA1 protein, human