Parkin' control: regulation of PGC-1α through PARIS in Parkinson's disease

Abstract

Summary and comment on a recent Cell paper entitled ‘PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson’s disease’ (Shin et al., 2011).

Fig. 1.

Parkin regulates the proteasomal degradation of PARIS and PGC-1α-dependent mitochondrial biogenesis. (A) Normal physiological conditions that maintain mitochondrial homeostasis: PINK1 recruits parkin to the mitochondria, where these two proteins interact to eliminate abnormal mitochondria through mitophagy. Alterations in mitochondrial membrane potential (ΔΨm; a key indicator of mitochondrial physiology and cell viability) initiate the PINK1-parkin cascade of events that lead to mitophagy. Furthermore, parkin ubiquitylates and thereby promotes proteasomal degradation of PARIS. Because PARIS represses the expression of PGC-1α, degradation of PARIS by parkin allows PGC-1α-dependent gene expression and enables mitochondrial biogenesis. Parkin seems to be an integral regulator of mitochondrial homeostasis, controlling both degradation and biogenesis. (B) Loss of parkin function as a result of familial mutations (in the case of AR-PD) or aging, environmental or cellular stress (in the case of sporadic PD) leads to the accumulation of abnormal mitochondria, owing to faulty mitophagy. In addition, PARIS accumulates and represses PGC-1α, preventing mitochondrial biogenesis. Loss of parkin function does not tip the balance between mitochondrial biogenesis and degradation to either side, but leads to a general breakdown of mitochondrial homeostasis that can ultimately lead to PD.