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

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2024 · $665,971

## Abstract

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.

## Key facts

- **NIH application ID:** 10877503
- **Project number:** 1R01NS133187-01A1
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** DAVID K. SIMON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $665,971
- **Award type:** 1
- **Project period:** 2024-03-15 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877503

## Citation

> US National Institutes of Health, RePORTER application 10877503, Targeting the FBXW7/PGC1 Pathway as a Therapeutic Strategy for Parkinson's Disease (1R01NS133187-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10877503. Licensed CC0.

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