To slow the progression of aging and age-related diseases such as Parkinson’s disease, we seek to improve
mitochondrial quality control, a mechanism that declines with age, through enhancing the removal of damaged
mitochondria by modulating mitochondrial quality control mechanisms such as Mitophagy.
Improved mitochondrial quality control restores efficient energy production, and helps return the
cell to its normal state of homeostasis.
Multiple genetic mutations in mitochondrial pathways cause genetic forms of Parkinson’s disease and
damaged mitochondria accumulate in idiopathic Parkinson's disease. Our hypothesis is that
increasing mitophagy to recycle these damaged mitochondria will increase the number of healthy
mitochondria and can counteract this key deficit in Parkinson’s disease brains.
Rationale for Top Targets
Parkin is an enzyme in cells that tags outer membrane proteins on damaged mitochondria and
thereby sets off repair or recycling of the damaged mitochondria. Mutations in the parkin gene which
make it dysfunctional cause Parkinson’s disease in humans, suggesting this enzyme is key for keeping
susceptible cells healthy. Accordingly, increasing levels of parkin protects against models of disease
in several animal species, from fruit fly and worm to non-human primates and human cells.
To maintain homeostasis, there are always opposing forces in living cells. An opposing enzyme to parkin
is USP30, which removes the tags attached by parkin and slows the repair and recycling mechanisms.
In fruit flies, decreasing USP30 can offer protection against mitochondrial dysfunction.
We look to translate these breakthrough discoveries to human medicines by activating parkin or inhibiting
USP30 using small molecules.