Characterization of the differential susceptibility of dopamine neuronal populations in a mouse model of Parkinson's disease.

摘要

Parkinson's disease (PD) is a neurodegenerative disorder that causes severe motor impairments due to progressive loss of nigrostriatal (NS) dopamine (DA) neurons. Abnormal DA metabolism has been proposed to underlie the degeneration of these neurons, but not all DA neurons are affected to the same extent in PD. There is severe loss of NSDA neurons, adjacent mesolimbic (ML) DA neurons are less severely affected and tuberoinfundibular (TI) DA neurons remain intact. The reason for this differential susceptibility amongst DA neurons is unknown. Elucidating mechanisms by which some neurons are preferentially lost while others are protected should lead to discovery of protective factors that can be translated into therapies for PD.;The experiments in this dissertation characterize a model for PD using the toxin 1-methyl,4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that mimics the differential susceptibility of DA neuronal populations seen in PD. In the MPTP mouse model, NSDA neurons are highly susceptible, while MLDA neurons are less damaged and TIDA neurons remain fully protected. Furthermore, the immediate response of these neuronal populations suggests that MLDA neurons don't lose as much DA as NSDA neurons immediately following treatment with MPTP, suggesting there might be heterogeneous populations of MLDA neurons, i.e. one that is susceptible and one that is resistant. On the other hand, TIDA neurons initially respond to MPTP treatment in a similar fashion to NSDA neurons, but rapidly recover. The recovery of these neurons from MPTP-induced DA loss is dependent on synthesis of new proteins following MPTP treatment. It is therefore likely that TIDA neurons upregulate the expression of proteins that allow for this recovery.;Microarray analysis of mRNA expression in NSDA and TIDA neurons reveal several important pathways and factors that may protect TIDA neurons after exposure to MPTP. One of the genes upregulated in TIDA neurons following MPTP treatment is the protective protein parkin. Mutations in this gene cause autosomal recessive PD and increased expression of this protein infers protection to cells in a variety of models, leading to the hypothesis that parkin upregulation may contribute to the recovery of TIDA neurons following MPTP treatment.;This hypothesis is tested by two separate approaches: exposing parkin knock out (KO) mice and wild type (WT) littermates to MPTP and stereotaxically injecting WT C57bl/6 mice with lentiviral particles expressing parkin shRNA in order to transiently knock down (KD) the expression of parkin. Animals receiving parkin shRNA lentivirus, but not parkin KO show stunted recovery of DA in response to MPTP treatment, suggesting parkin may be essential for the recovery of these neurons. Elucidating factors that are responsible for differential susceptibility to mitochondrial Complex I inhibition may be further translated into neuroprotective strategies that can prevent the ongoing degeneration of DA neurons in PD.