Enhancing Mitochondria Quality Control in Parkinson’s via Activation of the Caseinolytic Peptidase

Study Rationale:                   
Reinforcement of mechanisms that maintain the health of the cell’s energy generator, its mitochondria, may combat age-related diseases including Parkinson’s disease (PD). We have uncovered evidence that mitochondria use a signaling program coordinated by an enzyme called caseinolytic peptidase (CLPP) to repair and regenerate themselves. Increasing CLPP levels activated two important signaling processes linked to mitochondrial health and self-repair. Of particular importance, increasing the levels of the CLPP enzyme rescued PD-like health problems in model systems. Natural antibiotics that activate CLPP have already been discovered and shown to be biologically active and safe to administer to pe-clinical models.

Hypothesis:
Enhancing CLPP activity has the potential to increase mitochondrial self-repair and therefore overcome mitochondrial function defects associated with Parkinson’s disease.

Study Design:
We will monitor and change the amount of CLPP that cells express as well as CLPP’s activation using the previously discovered antibiotics and cells donated by living PD patients (with genetic and non-genetic forms of PD). We will evaluate the potential benefits of CLPP as a PD therapeutic target by correlating CLPP levels to severity of PD signs and measuring specific CLPP-dependent effects on mitochondrial self-repair.

Impact on Diagnosis/Treatment of Parkinson’s Disease:             
Positive outcomes in these studies will provide important proof-of-concept data to support further pursuit of CLPP as a therapeutic target for PD. As mitochondrial dysfunction is associated with Parkinson’s, protecting these cellular players may help keep cells healthy and slow Parkinson’s progression.

Next Steps for Development:
Future work would involve testing the ability for CLPP activation to combat Parkinson’s in human nerve cells and relevant whole-organism models of PD.

Additional Support:
This project was selected for a Stern Discovery Award with support from the former Michael Stern Parkinson's Research Foundation, which merged with The Michael J. Fox Foundation in 2015.