Objective/Rationale:
Increasing evidence points to an important role of genetics in Parkinson’s disease (PD). Causative mutations (alterations in the DNA sequence) have been found in many so-called PARK genes. It is thus important to understand the role of these genes. Our research will be dedicated to understand the function of the protein FBXO7, encoded by the PARK15 gene, which has been associated with early-onset parkinsonism in humans.
Project Description:
To determine the function of FBXO7 in the brain, we will use a pre-clinical model, in which we delete the FBXO7 gene either systemically or in the substantia nigra, the region of the brain that is predominantly affected in PD patients. We will then examine the motor function of these models by subjecting them to tasks that will identify specific motor deficits. In addition, we will investigate what role FBXO7 plays in neurons. Our data support a direct functional relationship of FBXO7 and the proteasome, which constitutes an essential machinery in cells responsible for the degradation of unwanted or worn out proteins. Taken together, our research will investigate FBXO7’s contribution to PD symptoms and, in addition, examine if FBXO7 regulates the protein degradation machinery in the brain.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
By identifying FBXO7 as a player in parkinsonism, we will understand the impact of the gene on motor function and its associated brain regions. Hence, the FBXO7 gene could serve as a candidate gene for PD, as genetic variants allow for the diagnosis of PD or may point to susceptibility toward the disease. Also, by deciphering an FBXO7 pathway regulating proteasome function, we will possibly identify novel leads to develop therapeutic strategies.
Anticipated Outcome:
With our research, we will generate understanding of how the dysfunctional FBXO7 gene contributes to PD. Not only will we be able to establish a relationship between this gene and PD symptoms, but we will also learn how disrupted FBXO7-dependent molecular processes in the brain add to this motor disorder. By identifying and knowing the players involved in PD, we hope to unravel particularly vulnerable events in the brain.