Mitochondrial dysfunction and oxidative stress play key roles in Parkinson’s disease (PD). PGC-1a is a master
regulator of mitochondrial biogenesis and antioxidant defenses. PGC-1a deficiency plays a key role in
dopaminergic (DA) neuronal survival, including vulnerability to a-synuclein (aSyn) toxicity, and also potentially in
Alzheimer’s disease. However, viral vector mediated overexpression of PGC-1a at high levels causes DA
neurons to degenerate and increases susceptibility to MPTP toxicity. Thus, harnessing the therapeutic potential
of PGC-1a likely requires normalization (or only mild elevation) of its expression levels in neurons. Achieving this
requires a better understanding of mechanisms regulating PGC-1a. We hypothesize that chaperone-mediated
autophagy (CMA) regulates PGC-1a indirectly by regulating FBW7, a multi-subunit E3 ubiquitin ligase that
promotes the degradation of critical regulatory proteins, including PGC-1a. We have found that SCFFBW7 harbors
the perfect CMA consensus sequence, “KFERQ”, and that increasing CMA decreases FBW7 and increases
PGC-1a protein levels. We hypothesize that CMA degrades FBW7, thus reducing UPS-mediated degradation of
PGC-1a:
¿CMA ¿ ¿ FBW7 ¿ ¿ PGC-1a
. 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-1a, and thus may represent a homeostatic mechanism for
maintaining stable levels of PGC-1a activity. We now propose first to analyze molecular mechanisms that
regulate FBW7 and PGC-1a, and then will specifically test our hypothesis that reducing SCFFBW7 in DA neurons
will protect against aSyn toxicity in a mouse model of PD.