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- Title
- The role of parkin in the recovery of central dopamine neurons from acute neurotoxicant exposure
- Creator
- Benskey, Matthew John
- Date
- 2013
- Collection
- Electronic Theses & Dissertations
- Description
-
Parkinson Disease (PD) pathology is associated with the selective degeneration of nigrostriatal dopamine (NSDA) neurons, while the tuberoinfundibular DA (TIDA) neurons of the hypothalamus remain intact. The same pattern of selective degeneration has been observed following exposure to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyradine (MPTP), a mitochondrial complex I inhibitor which recapitulates many of the molecular pathologies associated with PD. The purpose of this dissertation is to...
Show moreParkinson Disease (PD) pathology is associated with the selective degeneration of nigrostriatal dopamine (NSDA) neurons, while the tuberoinfundibular DA (TIDA) neurons of the hypothalamus remain intact. The same pattern of selective degeneration has been observed following exposure to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyradine (MPTP), a mitochondrial complex I inhibitor which recapitulates many of the molecular pathologies associated with PD. The purpose of this dissertation is to identify early molecular events that underlie TIDA neuron recovery from toxicant exposure and adapt these mechanisms in an attempt to rescue NSDA neurons from toxicity. NSDA neurons show loss of axon terminal DA concentrations following acute (20mg/kg; s.c.) and chronic (10 x 20mg/kg; s.c. over 35 days) MPTP administration and exhibit cell death following chronic MPTP administration. In contrast, TIDA neurons show no loss of axon terminal DA concentrations or cell death following acute or chronic MPTP exposure. The recovery of TIDA neurons is independent of extrinsic factors such as decreased toxicant exposure or hormonal activation. TIDA neuron recovery is associated with an increase in the PD-associated proteins, parkin and ubiquitin carboxy-terminal hydrolase L-1 (UCHL-1) within the arcuate nucleus (ARC) 24 h following MPTP. Additionally, parkin protein concentrations remain elevated in the ARC for up to 22 days following chronic MPTP administration. In contrast, the susceptibility of NSDA neurons is associated with decreased expression of both parkin and UCH-L1. The high correlation between the presence of the parkin protein and the recovery of DA neurons from MPTP toxicity is consistent with a role of parkin in DA neuron survival. In order to determine if parkin is necessary and sufficient in the recovery of TIDA neurons following MPTP, recombinant adeno-associated viral (rAAV) vectors containing parkin shRNA or a scrambled shRNA were created. Mice received stereotaxic ARC injections of rAAV containing either parkin shRNA or scrambled shRNA (250nl/side; 3.5x1013vg/ml), or remained naïve to surgery, and were administered a single injection of MPTP (20mg/kg; s.c.) 30 days following rAAV surgery. Twenty-four h post-MPTP, TIDA neurons were able to recover axon terminal DA concentrations following MPTP in control and scrambled shRNA treated animals. However, axon terminal DA was significantly reduced 24 hr following MPTP exposure following knockdown of parkin in TIDA neurons. To determine if parkin overexpression would protect NSDA neurons from MPTP toxicity, mice received unilateral stereotaxic injection of rAAV containing parkin into the substantia nigra (SN) (500nl; 3.4x1013vg/ml) and were administered a single injection of MPTP (20mg/kg; s.c.) 30 days following rAAV surgery. Twenty-four hours post-MPTP, parkin overexpression was unable to rescue MPTP-induced loss of DA in the striatum (ST), but did rescue MPTP-induced loss of tyrosine hydroxylase (TH) in the SN and ST. These findings are consistent with the following conclusions: 1) TIDA neuronal recovery from acute MPTP exposure is independent of extrinsic factors and is mediated by an intrinsic ability to increase expression of neuroprotective proteins, 2) The ability of TIDA neurons to up-regulate parkin is at least partially responsible for recovery of axon terminal DA following MPTP, 3) toxicant-induced loss of parkin contributes to MPTP toxicity within NSDA neurons.
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- Title
- Human genetic variations and their effect on common complex diseases
- Creator
- Li, Ming
- Date
- 2012
- Collection
- Electronic Theses & Dissertations
- Description
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BACKGROUND: The genetic etiology of common complex diseases has been extensively studied during the past few years. Though many causal genetic variants have been identified, they account for only a small percentage of the estimated heritability of complex diseases, such as breast cancer and cigarette smoking. It remains an open question about where the unexplained heritability lies and how to find it. The objective of this dissertation research is to examine three possible sources of such...
Show moreBACKGROUND: The genetic etiology of common complex diseases has been extensively studied during the past few years. Though many causal genetic variants have been identified, they account for only a small percentage of the estimated heritability of complex diseases, such as breast cancer and cigarette smoking. It remains an open question about where the unexplained heritability lies and how to find it. The objective of this dissertation research is to examine three possible sources of such unexplained heritability: 1) the association between copy number variants and breast cancer, 2) the association between gene-gene interactions and cigarette smoking, and 3) the association between functional rare variants and a simulated quantitative trait. METHODS: To detect copy number variants in breast cancer, we examine a breast cancer dataset from the National Cancer Institute and apply a hidden Markov model. To detect gene-gene interactions that are associated with cigarette smoking, we examine a genome-wide dataset from the Study of Addiction: Genetics and Environment and apply a forward U-test. To detect functional rare variants, we examine a dataset from Genetic Analysis Workshop 17 and apply an aggregating U-test. RESULTS: In the breast cancer study, we detect five genomic regions on chromosome 2, 4, 6, 12, and 13. In the cigarette smoking study, we detect two single nucleotide polymorphisms (SNPs) with potential interactions. These two SNPs are located in genes CHRNA5 and NTRK2. In the quantitative trait study, we show that the aggregating U-test has a greater power to detect functional rare variants than a commonly used approach, QuTie. CONCLUSIONS: Our findings from the breast cancer study suggest that structural changes of these genomic regions may contribute to the development of breast cancer. Our findings from the cigarette smoking study indicate that the joint action between genes CHRNA5 and NTRK2 may contribute to the development of cigarette smoking behavior. These proposed methods provide useful tools to detect various types of human genetic variations underlying complex diseases.
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- Title
- Towards a pragmatic theory of medical explanations of disease
- Creator
- DeCoster, Barry
- Date
- 2006
- Collection
- Electronic Theses & Dissertations