Study Rationale:
Loss-of-function mutations in PINK1 are causally linked to early-onset Parkinson’s disease (PD). MJFF funded the generation and initial characterization of PINK1 knockout (KO) models, which reproduce the age-dependent loss of the majority of dopamine neurons, which is the primary neuropathological feature of PD. PINK1 KO models also develop locomotor deficits around age seven months. The goal of this project is to advance the PINK1 KO model by determining the sequence, magnitude and location of potential pathologies in spinal cord, peripheral nerves or muscles and their correlation with loss of dopamine neurons in the brain.
Hypothesis:
We hypothesize that PD-linked PINK1 mutations cause the accumulation of dysfunctional mitochondria or other pathology in neurons with long axons, such as dopamine neurons of the substantia nigra or lower motor neurons in the spinal cord.
Study Design:
The deliverable for this study is a comprehensive analysis of the cause of the locomotor deficit and its time course relative to the nigral cell loss in PINK1 KO models. Before, during and after onset of the locomotor deficits, electrophysiological recordings will be performed on the sciatic nerve then histopathological, immunohistochemical and biochemical studies will be performed on spinal cord, muscle and sciatic nerve to map the sequence and location of the electrophysiological, pathological and biochemical changes that can serve as endpoints for testing interventions.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
This project will help to determine if the molecular mechanisms of the locomotor deficits in PINK1 KO models are the same mechanisms as the dopamine neuron loss caused by PD-linked mutations in PINK1.
Next Steps for Development:
Our studies are important for designing and interpreting future studies to evaluate interventions.