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Funded Studies

Targeting the Mitochondrial Unfolded Protein Response in Alpha-synuclein-induced Parkinson's Disease

Study Rationale:
The mitochondrial (powerhouse of the cell) unfolded protein response (mtUPR) is the first defense mechanism for maintaining proper quality of proteins within the mitochondria. Defects in mtUPR have been associated with neurodegeneration. Preliminary studies found that Clpp (a primary component of mtUPR) is decreased in dopamine neurons expressing alpha-synuclein wildtype or the A53T mutant and in fibroblasts (connective tissue) from those with Parkinson's disease (PD). Consistently, the immunodensity of Clpp was greatly reduced in the substantia nigra (brain region that controls movement; SN) of PD post-mortem brains when compared to that of age- and gender-matched normal individuals. Thus, we propose the involvement of Clpp-mediated mtUPR in the pathogenesis of alpha-synuclein-associated PD.

We hypothesize that impairment of mtUPR by alpha-synuclein causes mitochondrial dysfunction, which contributes to the neuropathology of PD.

Study Design:
To test our hypothesis, we will first characterize time course changes of key components of mtUPR in alpha-synuclein pre-clinical models. We will then determine whether increases in Clpp levels by injecting a virus can reduce mitochondrial dysfunction, behavioral deficits and neuropathology in the alpha-synuclein pre-clinical model.

Impact on Diagnosis/Treatment of Parkinson's disease:
The findings obtained from this study will advance our understanding of the pathogenesis of PD and reveal novel therapeutic targets for treatment of PD.

Next Steps for Development:
Successful completion of this proposed study will guide us to develop activators of Clpp as a potential strategy to reduce PD-associated neuropathology.


  • Xin Qi, PhD

    Cleveland, OH United States

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