Funded Studies
Study Rationale:
Rare mutations in the PINK1 gene cause familial (inherited) Parkinson's disease (PD). However, it is not known if PINK1 contributes to the development of idiopathic (no known cause) PD. Studies on the function of PINK1 suggest that it plays a role in the breakdown of damaged mitochondria, the energy factories of cells, through a process known as autophagy. Emerging evidence indicates that autophagy may be broadly impaired in PD, resulting in the accumulation of damaged mitochondria in cells. In several pre-clinical models of PD, decreasing PINK1 levels in dopamine-producing neurons accelerates their death, a hallmark of PD, whereas increasing PINK1 levels protects them.
Hypothesis:
Since increasing PINK1 activity has been shown to be therapeutic in pre-clinical models of PD, we hypothesize that PINK1 activation may be decreased in PD cells, and that targeting PINK1 may be a possible therapeutic strategy for the treatment of PD.
Study Design:
To investigate whether PINK1 activity is abnormal in PD, we will assess the extent and rate of PINK1 activation in living cells cultured from individuals with PD and individuals without PD. Our approach is to first generate antibody-like probes (immune system protein tags) that can bind to and label PINK1 in living cells without off-target effects. We will then use these PINK1 probes in cells from individuals with PD and those from individuals without PD to visualize the accumulation of PINK1 in mitochondria and to track the amount of PINK1 present in mitochondria over time, which cannot be done using current technologies. From these data, we will determine if PINK1 activation is significantly different in cells from individuals with PD.
Impact on Diagnosis/Treatment of Parkinson's Disease:
Discovery of whether (and how) PINK1 activation is broadly affected in PD will greatly assist with the following: 1) determining if drugs that target PINK1 could have a broad use for treating PD and 2) producing better drugs that target PINK1 activity.
Next Steps for Development:
If we find that PINK1 activation is reduced in cells from individuals with PD, we will strive to create new drugs based on our antibody-like PINK1 probes. When these PINK1-targeted drugs are administered to pre-clinical models of PD, the drugs should bind to PINK1 and cause a specific increase in its activity.