Parkinson’s disease (PD) is the second most common neurodegenerative disease. It is estimated that 7-10 million individuals suffer from the disease worldwide. Most cases are likely to result from the intersection of three risk factors: a genetic mutation, an environmental toxin, and advanced age. Although there are many treatments for the symptoms of PD, none appear to have a significant effect on its progression. Such treatments are urgently needed. PD is associated with a range of neurological dysfunctions and associated neuropathology. The precise relationship among most of these dysfunctions and the attendant pathology is not yet clear. However, many of the cardinal motor symptoms of PD appear to result from the loss of dopamine (DA) neurons with axons projecting from the substantia nigra (SN) onto the medium spiny neurons of the striatum and dendrites projecting into the SN pars reticulata where they can influence the basal ganglia output to thalamus and cortex. Although there are many drugs that are used to treat PD such as DA precursors, DA receptor agonists, cholinergic agents etc, there are two non-drug approaches which are thought to be effective clinically, electroacupuncture (EA) and exercise. However, although the clinical literature suggests efficacy, the mechanism for these two approaches is unclear and is the subject of the current preclinical proposal. Whereas the etiology of DA degeneration is unknown, prime candidates for a final common pathway are ER stress, the unfolded protein response (UPR), and mitochondrial dysfunction. Mitochondrial dysfunction and energy failure have been repeatedly implicated as the cause of the death of DA neurons in PD, as well as major causes of age-related neural dysfunction. Some toxins used to model DA loss in PD, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and rotenone, impair respiratory chain function by inhibiting complex I. In further support for a “mitochondrial genetics” hypothesis for PD pathophysiology, Bender et al (2006) reported higher levels of mitochondrial DNA deletions in nigral neurons from PD patients. Moreover, both Bender et al. (2006) and Kraytsberg et al. (2006) reported higher levels of mitochondrial DNA deletions in nigral neurons of aged humans with sharp elevations starting shortly before age 70. This correlates with the known risk factor of age in PD. In this study, we plan to identify novel neuroprotective strategies for PD. Our focus is aimed to establish the neuroprotection-based therapeutic strategies from two aspects: (1) to establish a well-characterized model of EA on the neuroprotective effects in PD mice. (2) to examine the effects of exercise in PD mice and to determine the most effective exercise paradigm using the running wheel. (3) to explore the impact of EA and exercise on the effects of MPTP on mitochondrial function and on ER stress.
|Effective start/end date||8/1/17 → 7/31/18|
- Parkinson’s disease
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