R01; National Institute of Neurological Disorders and Stroke
Targeting the FBXW7/PGC1 Pathway as a Therapeutic Strategy for Parkinson's Disease
Principal Investigator(s): David K Simon, Wenyi Wei
PGC-1alpha regulates mitochondrial synthesis, and a deficiency PGC-1alpha may play a role in Parkinson’s. However, too much PGC-1alpha also can have deleterious effects, so understanding the mechanisms for regulating levels of PGC-1alpha is important in order to potentially target this pathway as a therapeutic strategy in Parkinson’s. We have identified a novel regulatory pathway linking chaperone mediated autophagy to PGC-1alpha levels mediated by FBXW7. This award will fund studies to better understand this regulatory pathway and to test novel strategies that target this pathway for potential neuroprotection in Parkinson’s.
R21
VPS35 as a Therapeutic Target in Parkinson's Disease
Principal Investigator(s): David K Simon, Simona Eleuteri
A key pathological feature of Parkinson disease (PD) is the accumulation of oligomeric and aggregated forms of alpha-synuclein (αSyn) in intracellular inclusions. VPS35 is a retromer subunit involved in multiple protein degradation pathways, including degradation of αSyn. Mutations in VPS35 are a cause of late-onset autosomal dominant PD. It has been demonstrated that lentiviral overexpression of VPS35 protein in the brain attenuates the accumulation of αSyn protein in αSyn transgenic mice. Given these converging data, pharmacologically increasing levels of VPS35 may be a potential disease-modifying strategy in the treatment of PD.
USP30 Inhibition as a Therapeutic Strategy in Parkinson's Disease
Principal Investigator(s): David K Simon
Owens Family Foundation Award
Weston Brain Institute Advisor Fellowship Award
Recipient: David K Simon