PGC ‐1α regulation by FBXW7 through a novel mechanism linking chaperone‐mediated autophagy and the ubiquitin‐proteasome system

Peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC‐1α) is a key regulator of mitochondrial biogenesis and antioxidative defenses, and it may play a critical role in Parkinson's disease (PD). F‐box/WD repeat domain‐containing protein (FBXW7), an E3 protein ligase, promotes the degradation of substrate proteins through the ubiquitin‐proteasome system (UPS) and leads to the clearance of PGC‐1α. Here, we elucidate a novel post‐translational mechanism for regulating PGC‐1α levels in neurons. We show that enhancing chaperone‐mediated autophagy (CMA) activity promotes the CMA‐mediated degradation of FBXW7 and consequently increases PGC‐1α. We confirm the relevance of this pathway in vivo by showing decreased FBXW7 and increased PGC‐1α as a result of boosting CMA selectively in dopaminergic (DA) neurons by overexpressing lysosomal‐associated membrane protein 2A (LAMP2A) in TH‐Cre‐LAMP2‐loxp conditional mice. We further demonstrate that these mice are protected against MPTP‐induced oxidative stress and neurodegeneration. These results highlight a novel regulatory pathway for PGC‐1α in DA neurons and suggest targeted increasing of CMA or decreasing FBXW7 in DA neurons as potential neuroprotective strategies in PD.