Early-Onset Parkinson's Disease Is a Mitochondrial Disease: A Nigral Mitochondrial Cytopathy

Topic Area: Mitochondrial Disease. Our proposed studies are centered on the fact that early-onset Parkinson's disease (EOPD) is clearly a mitochondrial disease as demonstrated by genetic mutations in the PINK1 and PARK2 genes and the critical roles the proteins play in mitochondrial quality control. EOPD is a devastating disorder clinically characterized by a visible movement disorder with a usual onset before the age of 50 years. In addition, many military Service members are exposed to a multitude of environmental agents, and in recent combat operation many Service members have experienced traumatic brain injuries, either of which may result in clinical parkinsonism. Our aims could shed insight into these other forms of parkinsonism that would be commonly seen in the military population. To date, a limited number of gene mutations (changes in our DNA) have been identified that directly cause EOPD in patients. Our work and others have shown that the principal genes involved play an important role in keeping the cell healthy. A specific population of one of our cell building blocks, known as the mitochondria, is continually being renewed and degraded. In patients with EOPD, there appears to be a breakdown in this quality control (QC) pathway. The proposed studies will identify and characterize the different proteins of this QC pathway; in addition, we will look at the DNA encoding these proteins and identify if there is any DNA changes that cause EOPD in our patient samples collected at the Mayo Clinic. We will use a battery of different genetic, cell, and model-based tests to confirm the genes and the DNA changes play a role in EOPD and other mitochondria-related diseases. The identification of the genes/genetic mutations that cause disease will help the clinician improve diagnostic/prognostic outcomes and help direct in vitro and in vivo model generation for determining targeted therapeutic development for both PD and related disorders caused by a breakdown of the mitochondrial quality control pathway.