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PGC-1a Therapy for Parkinson Neurodegeneration

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Annual rept. 30 May 2014-29 May 2015

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Currently there are no natural disease-modifying treatments for Parkinsons disease PD. Microarray analyses have implicated decreased expression of proliferator-activated receptor gamma co-activator-1 alpha PGC-1 alpha as a potential pathobiologic link to the mitochondrial dysfunction in Parkinsons disease PD. In vitro and in vivo studies show that PGC-1 deficiency increases the susceptibility to MPTPinduced neurotoxicity, and enhanced PGC-1 levels protect neural cells from oxidative stress or -synuclein-mediated neuronal death. Collective evidence to date, therefore, strongly suggests that PGC-1 is a promising therapeutic target within the central nervous system CNS for the treatment of PD. Herein we hypothesize that pharmacologically titrated upregulation of PGC-1 will provide protection against neurodegeneration in PD. Our goal is to modify disease progression by modulating PGC-1 levels with CNS-targeted small molecule therapeutics at an early stage of PD pathogenesis. We have identified that fenofibrate, an FDA approved drug, induces PGC-1 expression in CNS cells and exerts both cytoprotective and anti-inflammatory effects. Given the demonstrated safety profile of fenofibrate in vivo, we will test whether fenofibrate offers therapeutic potential in PD models as a prelude to a potential clinical study in patients. In this reporting period, we have demonstrated that fenofibrate mediates anti-inflammation in a PGC-1-dependent, PPAR-independent manner. We further evaluated in vivo efficacy of fenofibrate in a MPTP mouse model of PD.

Subject Categories:

  • Biochemistry
  • Anatomy and Physiology
  • Medicine and Medical Research
  • Pharmacology

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