Parkinson disease (PD), the second most prevalent neurodegenerative disorder, is most commonly diagnosed in elderly individuals and is characterized by manifestation of motor deficits such as bradykinesia, postural instability, resting tremor, and shuffling gait. These motor symptoms of PD arise when dopamine (DA) neurons in the nigrostriatal DA (NSDA) pathway degenerate, causing loss of basal ganglia regulation of voluntary motor coordination. Other DA neuronal pathways in the central nervous system are less affected by neuronal death, however: mesolimbic DA (MLDA) neurons are less vulnerable to loss in PD. Therefore, we seek to understand how MLDA neurons resist degeneration. Since Lewy bodies, which are proteinaceous deposits of misfolded and aggregated proteins, are the hallmark pathology of PD, we predict that major deficits in protein degradation are involved in development and progression of this disease. MPTP exposure in rodents recapitulates loss of DA and oxidative stress observed in patients with PD and can also be used to recapitulate the differential susceptibility of NSDA and MLDA neurons. A gene found mutated in a rare case of familial PD called ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is involved in proteostasis functioning as a deubiquitinating enzyme to maintain pools of available monomeric ubiquitin. UCH-L1 protein is decreased in the SN of mice exposed to MPTP. The goal of this Dissertation research was to investigate the role of UCH-L1 in influencing susceptibility of NSDA and MLDA neurons to acute neurotoxic insult, and if aging plays a role in determining vulnerability of NSDA and MLDA neurons or expression and function of UCH-L1. The results reveal that UCH-L1 expression and function are maintained in non-susceptible MLDA neurons, which corresponds to the pattern of MLDA susceptibility to MPTP exposure. UCH-L1 expression is not affected by advanced age in NSDA or MLDA neurons, despite impairment of UPS function in cell body regions with advanced age. Additionally, aged mice are not more sensitive to MPTP exposure, but astrocytes in the axon terminal regions of MLDA neurons retain the protective ability to metabolize DA after MPTP administration, highlighting their protective role and potential contribution to differential susceptibility. These studies shed light on the potential contribution of the PD-linked neuronal deubiquitinating enzyme UCH-L1 to selective vulnerability in PD.
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