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Review
. 2019 Jul 13;705:7-13.
doi: 10.1016/j.neulet.2019.04.029. Epub 2019 Apr 14.

Therapeutic Approaches to Enhance PINK1/Parkin Mediated Mitophagy for the Treatment of Parkinson's Disease

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Review

Therapeutic Approaches to Enhance PINK1/Parkin Mediated Mitophagy for the Treatment of Parkinson's Disease

Silke Miller et al. Neurosci Lett. .

Abstract

The discovery of rare familial monogenic forms of early-onset Parkinson's disease has led to the identification of a mitochondrial quality control process as a key player in this disease. Loss-of-function mutations in the genes encoding PINK1 or Parkin result in insufficient removal of dysfunctional mitochondria through autophagy, a process termed mitophagy. Understanding the mechanism of this process and the function of its two key players, PINK1 and Parkin, has led to the discovery of new therapeutic approaches. Small molecule activators of mitophagy, either activating PINK1 or Parkin directly or inhibiting Parkin's counterplayer, the ubiquitin-specific protease USP30, are in preclinical development. To enable clinical success of future small molecule mitophagy enhancers, biomarkers for mitochondrial integrity and mitophagy are being developed. Only a few years after the discovery of mitophagy deficits in Parkinson's disease, research of the underlying mechanisms, drug discovery of modulators for this mechanism and identification of biomarkers provide new avenues towards the development of disease-modifying therapies.

Keywords: Mitophagy; PINK1; Parkin; Parkinson’s disease; Small molecule; USP30.

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