Targeting the FBXW7/PGC1 Pathway as a Therapeutic Strategy for Parkinson's Disease

Mitochondrial dysfunction and oxidative stress play key roles in Parkinson’s disease (PD). PGC-1α is a master regulator of mitochondrial biogenesis and antioxidant defenses. PGC-1α deficiency plays a key role in dopaminergic (DA) neuronal survival, including vulnerability to α-synuclein (αSyn) toxicity, and also potentially in Alzheimer’s disease. However, viral vector mediated overexpression of PGC-1α at high levels causes DA neurons to degenerate and increases susceptibility to MPTP toxicity. Thus, harnessing the therapeutic potential of PGC-1α likely requires normalization (or only mild elevation) of its expression levels in neurons. Achieving this requires a better understanding of mechanisms regulating PGC-1α. We hypothesize that chaperone-mediated autophagy (CMA) regulates PGC-1α indirectly by regulating FBW7, a multi-subunit E3 ubiquitin ligase that promotes the degradation of critical regulatory proteins, including PGC-1α. We have found that SCFFBW7 harbors the perfect CMA consensus sequence, “KFERQ”, and that increasing CMA decreases FBW7 and increases PGC-1α protein levels. We hypothesize that CMA degrades FBW7, thus reducing UPS-mediated degradation of PGC-1α: ↑CMA  ↓ FBW7  ↑ PGC-1α . FBW7 is a target of PRKN, with Prkn loss leading to increased FBW7 in Prkn-null mice, which in turn reduces levels of the anti-apoptotic factor Mcl-1. Furthermore, brain FBW7 levels are increased in PD patients with PRKN mutations. Thus, FBW7 is a potential therapeutic target in PD, but our understanding of mechanisms regulating FBW7 is limited. To this end, we have preliminary data implicating that p300/SIRT1 dependent regulation of FBW7 acetylation plays a potentially key role in regulating FBW7 levels. p300/SIRT1 also interact directly with PGC-1α, and thus may represent a homeostatic mechanism for maintaining stable levels of PGC-1α activity. We now propose first to analyze molecular mechanisms that regulate FBW7 and PGC-1α, and then will specifically test our hypothesis that reducing SCFFBW7 in DA neurons will protect against αSyn toxicity in a mouse model of PD.