Wednesday, February 5, 2025
2/5/2025
Project Summary The primary pathological hallmark of Parkinson's disease (PD) is degeneration of the nigrostriatal dopamine (DA) pathway, which underlies the motor impairments of PD. At present, the most common pharmacological treatment for PD is DA replacement using L-DOPA, a precursor for DA synthesis. Unfortunately, although L- DOPA and related pharmacological approaches treat symptoms, they do not alter disease progression. Moreover, dyskinesia is a common side effect of long-term L-DOPA administration. New approaches are therefore long overdue. Clinical and basic science research has shown that exercise, an adjunct, non- pharmacological treatment strategy can be beneficial for patients with PD. Our preliminary data from young male (10 week) and aged (12 month) female and male mice show that voluntary wheel running exercise boosts stimulated DA release in ex vivo striatal slices from runners (freely rotating wheel) compared to age-matched controls (locked wheel). These exercise studies were conducted in collaboration with Co-Investigators Moses Chao and Adam Mar. These studies also revealed an increase in brain-derived neurotrophic factor (BDNF) in the dorsal striatum of young male runners vs. controls. Implicating a causal role for BDNF, exercise-induced enhancement of DA release was lost in BDNF+/- mice, which have low levels of BDNF. Proposed experiments in this project will answer key questions using healthy, wild type (WT) mice, including whether axonal DA release in vivo is enhanced after exercise as seen in ex vivo slices, and whether exercise also boosts somatodendritic DA release in midbrain slices. The role of BDNF in all exercise-altered parameters will be assessed by comparing data from WT and BDNF+/- mice. Given that striatal DA release is enhanced by exercise in both sexes, but with some differences, all experiments will assess sex as a variable. In Aim 1, we will determine the influence of voluntary exercise (30 days) on striatal DA uptake in ex vivo slices and on axonal DA release in vivo using GRAB-DA with fiber photometry. In Aim 2, we will test the hypotheses that voluntary exercise boosts somatodendritic DA release and enhances striatal neuron plasticity in WT mice of both sexes, but is without effect in BDNF+/- mice. Motor tests will be conducted in all cohorts to enable comparison of exercise-altered physiology and motor performance. Aim 3 will assess benefits of exercise in a new genetic mouse model of PD: Parkin R275W mice. These mice were developed in the Sassone Lab in Milan using CRISPR/CAS9 to express the R275W mutation of PARK2, which is associated with early-onset PD. R275W mice show motor deficits and DA neuron degeneration at 12 months; preliminary data show that 30 days of exercise boosts striatal DA release in 12 month-old R275W mice, and that this is associated with motor improvement, even in this small pilot cohort. Overall, this project will provide novel mechanistic insight into processes that are enhanced by exercise, and could point to new therapeutic strategies for Parkinson's disease, as well as for other disorders that show improvement with exercise.
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