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Title: A study of the response of two patients with Parkinsonism to doses of ascorbic acid and thiamine
Creator: De Voe, Ruth Watkins
Date: 1956
Collection: Electronic Theses & Dissertations

Title: A role for DeltaFosB in the regulation of parkin in brain regions containing differentially susceptible dopaminergic neurons
Creator: Patterson, Joseph Robert
Date: 2016
Collection: Electronic Theses & Dissertations
Description: The hallmark pathologies of Parkinson disease (PD) are the formation of Lewy bodies and the progressive loss of nigrostriatal dopamine (NSDA) neurons. In mice, the NSDA neurons are preferentially damaged through exposure to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Another population of DA neurons that are initially damaged by MPTP, but are able to recover are the tuberoinfundibular DA (TIDA) neurons. Parkin is a product of the PARK2 gene, which is linked to...
Show moreThe hallmark pathologies of Parkinson disease (PD) are the formation of Lewy bodies and the progressive loss of nigrostriatal dopamine (NSDA) neurons. In mice, the NSDA neurons are preferentially damaged through exposure to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Another population of DA neurons that are initially damaged by MPTP, but are able to recover are the tuberoinfundibular DA (TIDA) neurons. Parkin is a product of the PARK2 gene, which is linked to autosomal recessive or juvenile PD. Parkin has multiple functions in neurons and is predicted to protect against the neurotoxic effects of MPTP. Potential transcription factors of parkin were identified using TFSEARCH, PROMO, and Patch 1.0, and refined to 11 based the transcription factor being identified in all three programs, being known to be found in the brain, and known to respond to a type of stress that MPTP could cause. The candidate transcription factors were examined at 6 h after MPTP in regions containing the cell bodies of TIDA and NSDA neurons. From these candidates, only FosB and ΔFosB have expression patterns that mirror parkin.Further examination of the temporal expression and cellular localization of FosB and ΔFosB after acute neurotoxicant administration were examined. Regions containing the cell bodies of the TIDA (arcuate nucleus; ARC) and NSDA (substantia nigra; SN) neurons were dissected and processed for Western blot analysis. The results reveal that expression of FosB and ΔFosB correlates with parkin, increasing in the ARC and not in the SN. Furthermore, total FosB protein was localized to nuclei of NSDA and TIDA neurons, and expression of each FosB and ΔFosB examined in cytoplasmic and nuclear fractions derived from the ARC and SN. Though the number of DA neurons expressing total FosB does not change at 6 h post-MPTP, ΔFosB does increase in the nuclear fraction from the ARC.AAV-mediated expression vectors were used to increase ΔFosB in the NSDA and TIDA neurons, in both cases, parkin increased about 2-fold. The dominant negative protein ΔJunD, which lacks a DNA binding domain, predominantly dimerizes with the FosBs and inhibits their ability to act as transcription factors was injected into the ARC. The AAV-ΔJunD virus blocked the increase of parkin after MPTP in the TIDA neurons. Taken together, the results support the role of FosB and ΔFosB as transcription factors of parkin, since they are predicted to bind the Park2 promoter, their expression correlates with the differential expression of parkin, increases prior to parkin, are present in nuclei of TIDA neurons, ΔFosB is sufficient to drive parkin expression, and ΔJunD blocks the increase of parkin in the ARC in response to MPTP.
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Title: Parkin mediated mitochondrial quality control in central dopamine neurons
Creator: Hawong, Hae-young
Date: 2014
Collection: Electronic Theses & Dissertations
Description: Parkinson disease (PD) is the second most common neurodegenerative disease. The hallmark pathology of PD is progressive degeneration of nigrostriatal dopamine (NSDA) neurons, but the hypothalamic tuberoinfundibular (TI) DA neurons remain intact. A similar pattern of susceptibility can be seen in these DA neuronal populations following single acute exposure to the mitochondrial Complex I inhibitor, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this dissertation, mitochondrial...
Show moreParkinson disease (PD) is the second most common neurodegenerative disease. The hallmark pathology of PD is progressive degeneration of nigrostriatal dopamine (NSDA) neurons, but the hypothalamic tuberoinfundibular (TI) DA neurons remain intact. A similar pattern of susceptibility can be seen in these DA neuronal populations following single acute exposure to the mitochondrial Complex I inhibitor, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this dissertation, mitochondrial structure and function in NSDA and TIDA axon terminals in WT mice were investigated. An increase in mitochondrial bioenergetics, mass, and mitophagosomes were observed in mitochondria derived from medial basal hypothalamus (MBH) containing TIDA neurons as compared to striatum (ST) containing NSDA neurons. The ultrastructure of the mitochondria from the two brain regions did not differ, but MBH had higher numbers of mitochondria per synaptosome than ST. Mitochondrial function differed depending on the brain regions in WT mice. However, mitochondria derived from ST and MBH responded to Complex I inhibition in a similar manner. This suggests that intrinsic differences in the sensitivity of mitochondrial electron transport chain (ETC) enzymes to neurotoxicant inhibition are not responsible for differential susceptibility of NSDA and TIDA neurons to MPTP.Parkin is a 52Kda cytosolic protein originally identified by linkage analysis in autosomal recessive early onset PD. Parkin is reported to mediate mitochondrial quality control through autophagy of mitochondria, and increased parkin expression is associated with resistance of TIDA neurons to acute MPTP exposure. Parkin may protect against DA neurodegeneration by maintaining mitochondrial homeostasis in central DA neurons. To test this hypothesis, mitochondrial structure and function in NSDA and TIDA neurons were investigated in parkin null mice. Reduced mitochondrial maximal and spare respirations, mitochondrial mass, number of mitochondria per synaptosome, and disrupted mitochondrial ultrastructure were all observed in the absence of parkin. These results suggest that impaired mitochondrial function is due to decreased numbers of high quality mitochondria in DA axon terminals in the ST of parkin deficient mice. This may be due to loss of parkin-mediated mitochondrial quality control in NSDA neurons. Parkin rescue via rAAV expression in the midbrain failed to alter impaired mitochondrial function in parkin null mice. However, parkin overexpression prevented inhibition of maximum and spare respiration by MPTP. These results suggest parkin overexpression maintained functional mitochondria likely through autophagy in response to acute neurotoxicant exposure. Therefore, loss of parkin mediated mitochondrial quality control may contribute to loss of NSDA neurons in a neurotoxicant model of DA neuronal degeneration in PD.
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Title: Deep brain stimulation of the subthalamic nucleus increases brain-derived neurotrophic factor in the context of synucleinopathy
Creator: Miller, Kathryn M.
Date: 2020
Collection: Electronic Theses & Dissertations
Description: Parkinson’s disease (PD) is the second most common neurodegenerative disorder behind Alzheimer’s disease, and is a major burden to society. PD is a progressive disorder resulting in a variety of symptoms including dementia, autonomic, and motor dysfunction; all contributing to a diminished quality of life for afflicted individuals. Current treatments help to restore motor function, however there are no disease-modifying treatments that halt or slow the progression of PD. The question of...
Show moreParkinson’s disease (PD) is the second most common neurodegenerative disorder behind Alzheimer’s disease, and is a major burden to society. PD is a progressive disorder resulting in a variety of symptoms including dementia, autonomic, and motor dysfunction; all contributing to a diminished quality of life for afflicted individuals. Current treatments help to restore motor function, however there are no disease-modifying treatments that halt or slow the progression of PD. The question of whether deep brain stimulation (DBS) of the subthalamic nucleus (STN) can be disease-modifying in PD remains unanswered. Preclinical studies link STN DBS-mediated neuroprotection of nigrostriatal dopamine neurons to brain-derived neurotrophic factor (BDNF) signaling. However, the impact of STN DBS on α-synuclein (α-syn) aggregation, inclusion-associated neuroinflammation, and BDNF levels have yet to be examined in the context of synucleinopathy.In this dissertation I examine the effects of STN DBS on BDNF in the preformed fibril synucleinopathy model. PFF injection resulted in accumulation of phosphorylated α-syn (pSyn) inclusions in the substantia nigra pars compacta (SNpc) and cortical areas. SNpc pSyn inclusions were associated with significantly increased major histocompatibility complex-II immunoreactive (MHC-II-ir) microglia, and intensity, complexity, and length of astrocytes. Rats with pSyn inclusions had less tyrosine hydroxylase (THir) SNpc neurons (≈18-33% decrease) reflecting loss of TH phenotype. STN DBS did not alter any of these pSyn inclusion-associated effects, and also did not impact the size or intensity of individual pSyn inclusions within the SNpc. The presence of pSyn inclusions did not alter total levels of BDNF protein in any of the structures evaluated. However, the normally positive association between nigrostriatal and corticostriatal BDNF levels was negatively impacted in PFF treated rats. Despite this, rats receiving both PFF injection and STN DBS exhibited significantly increased BDNF protein in the striatum, which partially restored the normal corticostriatal BDNF relationship.The rat α-syn PFF model provides a relevant preclinical platform to examine the impact of STN DBS on multiple potentially disease-modifying factors. Our results demonstrate that pSyn inclusions may alter anterograde BDNF transport. However, STN DBS retains the ability to increase BDNF within the context of synucleinopathy. Future studies will examine whether long-term STN DBS can prevent the nigrostriatal degeneration associated with longer post PFF injection intervals.
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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: Memory, metamemory and depression in Parkinson's disease
Creator: Coulter, Lila
Date: 1987
Collection: Electronic Theses & Dissertations

Title: Parametric study of Parkinsonian gait
Creator: Soutas-Little, Patricia
Date: 1990
Collection: Electronic Theses & Dissertations

Title: Study of tyrosine kinase like protein kinases : I.A novel role for mixed-lineage kinase 3 in mitochondria throught its interaction protein, adenine nucleotide translocase 2. ; II. Characterization of roc domain of parkinson's disease-associated kinase,...
Creator: Liou, Geou-Yarh
Date: 2007
Collection: Electronic Theses & Dissertations

Title: Is age just a number? : accounting for age when designing viral vectors for Parkinson's disease
Creator: Polinski, Nicole Kathleen
Date: 2016
Collection: Electronic Theses & Dissertations
Description: Parkinson’s disease (PD) is the second most common neurodegenerative disease with no disease-modifying therapy currently available. Viral vector-mediated gene therapy, however, is being tested in clinical trials as a method to slow disease progression. Although multiple clinical trials have tested the efficacy of this therapy for PD, all strategies have failed to provide adequate relief. Although possibly due to a variety of reasons, failing to consider aging as a covariate in preclinical...
Show moreParkinson’s disease (PD) is the second most common neurodegenerative disease with no disease-modifying therapy currently available. Viral vector-mediated gene therapy, however, is being tested in clinical trials as a method to slow disease progression. Although multiple clinical trials have tested the efficacy of this therapy for PD, all strategies have failed to provide adequate relief. Although possibly due to a variety of reasons, failing to consider aging as a covariate in preclinical trials could have contributed to these results. The importance of accounting for age when designing viral vectors for PD stems from the fact that age is the greatest risk factor for developing PD and age-related impairments in cellular processes overlap with steps of viral vector transduction. As a result, I sought to test whether advanced age impacts viral vector transduction efficiency. In the present dissertation, I tested the efficiency of four viral vector constructs in two systems of the brain involved in PD. Three pseudotypes of recombinant adeno-associated virus (rAAV2/2, rAAV2/5, rAAV2/9) and a lentiviral vector (LV) were chosen due to their use in clinical trials for PD, preclinical trials in PD animal models, or proposed use in clinical trials for PD. These viral vectors were injected into the substantia nigra pars compacta (SNpc) to transduce the nigrostriatal system—the system that degenerates in PD—or the striatum to transduce the striatonigral system—the system most often targeted in viral vector-mediated gene therapy clinical trials for PD. The first evidence for an age-related transduction deficiency came from observations that rAAV2/5 expressing green fluorescent protein (rAAV2/5 GFP) was deficient in transducing the aged as compared to young adult rat midbrain and nigrostriatal system two weeks post-injection. I continued this investigation by systematically characterizing the ability of rAAV2/2, rAAV2/5, rAAV2/9, and LV, all expressing GFP, to transduce the aged as compared to young adult rat nigrostriatal and striatonigral systems at one month post-injection when expression levels asymptote. I observed robust age-related deficiencies in the ability of rAAV2/2 and rAAV2/5 to transduce the nigrostriatal and striatonigral systems. Age-related deficiencies were also observed in rAAV2/9 and LV transduction; however, deficiencies were observed in the nigrostriatal but not striatonigral system with LV and vice versa with rAAV2/9. Taken together, these results indicate robust age-related transduction deficiencies that are structure- and vector-specific. The clinical relevance of this finding was investigated to determine whether the viral vector construct used in an upcoming clinical trial is similarly deficient in the aged striatonigral system. I found robust deficiencies in rAAV2/2 overexpressing glial cell line-derived neurotrophic factor (rAAV2/2 GDNF) in the injected striatum as well as in the ipsilateral anterograde structures, suggesting age may negatively impact an upcoming PD clinical trial. Finally, I sought to determine the mechanism of the age-related transduction deficiency of rAAV2/2 in the nigrostriatal system and uncovered a role for cell surface receptors in the deficiency. Taken together, the results of my experiments highlight the need to account for age when developing therapies for age-related neurodegenerative diseases. Specifically, age can greatly impact the ability of viral vectors to transduce brain systems involved in PD, with robust age-related deficiencies observed across multiple viral vectors, target structures, transgenes expressed, rat strains, and durations of expression. Furthermore, the mechanism of this deficiency may involve virion interactions with cell surface receptors. With this information, future clinical and preclinical studies using viral vectors in the aged brain may be able to circumvent age-related transduction deficiencies and develop a disease-modifying treatment for neurodegenerative diseases like PD.
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Title: A longitudinal study of Parkinsonian speech characteristics
Creator: Brinkman, Juliane Leigh
Date: 2014
Collection: Electronic Theses & Dissertations
Description: "The present study was conducted with two goals in mind. First, to determine whether acoustic variables can be used to differentiate PD [Parkinson's disease] speakers from healthy speakers during times before the clinical diagnosis of PD. Second, to determine the usefulness of acoustic variables for monitoring the disease progression of PD."--From abstract.

Title: Levodopa-induced dyskinesia : from aberrant presynaptic signaling to maladaptive postsynaptic plasticity
Creator: Sellnow, Rhyomi Charis
Date: 2018
Collection: Electronic Theses & Dissertations
Description: Parkinson’s disease (PD) is a neurodegenerative disorder that arises following the death of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). DAergic signaling from these neurons is required for proper signaling of the basal ganglia, a circuit that regulates habitual motor behaviors. As the SNc degenerates, DA signaling to the hub of the basal ganglia—the striatum—is drastically reduced. This progressive loss results in the development of parkinsonian motor symptoms,...
Show moreParkinson’s disease (PD) is a neurodegenerative disorder that arises following the death of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). DAergic signaling from these neurons is required for proper signaling of the basal ganglia, a circuit that regulates habitual motor behaviors. As the SNc degenerates, DA signaling to the hub of the basal ganglia—the striatum—is drastically reduced. This progressive loss results in the development of parkinsonian motor symptoms, including bradykinesia, tremor, and gait problems. To treat these symptoms, the DA precursor L-3,4-dihydroxyphenylalanine (L-DOPA) can be administered to reintroduce DA signaling in the striatum. Unfortunately, chronic treatment with L-DOPA inevitably leads to the development of new motor symptoms, called L-DOPA-induced dyskinesia (LID), in the majority of PD patients. LID development is a complex, multifaceted process. The aim of this dissertation is to elucidate the mechanism of LID by studying abnormal presynaptic signaling and the aberrant postsynaptic striatal plasticity induced in dyskinesia. First, we found that DA release from serotonin (5-HT) cells of the dorsal raphe nucleus (DRN) is a critical contributing factor to LID in a rat model of PD, and that regulation of DRN neurons blocks LID development. We showed this by using recombinant adeno-associated virus (rAAV) to express the DA autoreceptor D2Rs in DRN neurons, giving them ability to regulate abnormal DA release. Treatment with rAAV-D2Rs blocks LID development by decreasing DA efflux into the striatum. Second, we have characterized a novel postsynaptic molecular driver of LID, Nurr1. Nurr1 has been identified in genetic screens to be significantly upregulated in dyskinetic animal models. Therapies aimed at increasing Nurr1 are currently being investigated for PD, as the transcription factor is required for the health and long-term maintenance of the DA cells that degenerate in the disease. This dissertation provides evidence that Nurr1 plays a direct role in LID development. Viral expression of Nurr1 in the striatum can induce severe LID in a rat strain that is resistant to LID. Additionally, we showed that LID-associated Nurr1 expression is induced by direct stimulation of the pro-movement pathway of the basal ganglia. Finally, we determined that Nurr1 expression causes changes in both the activity and morphology of striatal medium spiny neurons (MSNs). We have shown that, independent of L-DOPA administration, Nurr1 causes altered striatal activity that mimics activity changes seen in dyskinetic animals. Ectopic Nurr1 expression also causes L-DOPA-independent decreases in dendritic spines. As dendritic spine plasticity is a hallmark of LID, our data suggests that Nurr1 plays a direct role in these maladaptive changes. Together, this dissertation provides compelling evidence for both presynaptic and postsynaptic mechanisms of LID development.
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Title: The temporal relationship between synucleinopathy, nigrostriatal degeneration, and neuroinflammation in the alpha-synuclein preformed fibril model of Parkinson's disease
Creator: Duffy, Megan Frances
Date: 2018
Collection: Electronic Theses & Dissertations
Description: Numerous studies have documented risk variants in immune genes and increased microglial inflammatory markers in the parenchyma and biofluids of Parkinson’s disease (PD) patients. Recently our lab has characterized a new rat model of PD induced by injection of α-syn preformed fibrils (α-syn PFFs). The PFF model more faithfully recapitulates key features of idiopathic PD: namely early development of Lewy body-like pathology in widespread, PD-relevant brain regions under the context of normal...
Show moreNumerous studies have documented risk variants in immune genes and increased microglial inflammatory markers in the parenchyma and biofluids of Parkinson’s disease (PD) patients. Recently our lab has characterized a new rat model of PD induced by injection of α-syn preformed fibrils (α-syn PFFs). The PFF model more faithfully recapitulates key features of idiopathic PD: namely early development of Lewy body-like pathology in widespread, PD-relevant brain regions under the context of normal levels of endogenous α-syn and protracted nigrostriatal degeneration over the course of 6 months. The distinct stages afforded by this model allow for investigation of neuroinflammation at different stages of synucleinopathy without the confound of α-syn pathology and degeneration occurring concurrently. First, I histologically examined the time course of synucleinopathy, microgliosis and nigral degeneration at monthly intervals. Microglia in the vicinity of Lewy body-like inclusions display significantly increased cell body area and observable differences in extent and thickness of branching at 2 months post-injection, months prior to degeneration. Interestingly, major-histocompatibility complex-II (MHC-II; present on antigen-presenting microglia) was significantly increased in PFF-injected animals compared to controls 3 months prior to degeneration and relatively absent during the interval of degeneration. Moreover, the number of microglia expressing MHC-II at 2 months was positively correlated with the number of Lewy body-like inclusions in the substantia nigra, similar to observations documented in human PD tissue. I next investigated the temporal profile of inflammatory cytokine expression in cerebrospinal fluid and plasma in the context of naïve aging animals and in PFF-injected animals. In the context of normal aging, tumor necrosis factor (TNF) and keratinocyte chemoattractant (KC/GRO) were significantly increased in aged animals compared to young and young-adult animals. In the synucleinopathy cohort when α-syn burden in the SN is greatest, I observed significant correlations between number of nigral α-syn inclusions and CSF levels of interferon-gamma (IFN-γ) were observed. At 4 months I continued to observe correlations between α-syn burden and CSF IFN-γ and TNF, and significantly elevated interleukin-6 in PFF animals compared to controls. During the interval of degeneration, significantly increased levels of interleukin-5 (IL-5), keratinocyte chemoattractant (KC/GRO), and TNF were observed, though cytokines did not correlate with magnitude of degeneration at this time point. These results suggest that a certain threshold of α-syn burden must be present in order for deviations in cytokine levels to be detected in early stages of disease and that overt differences in cytokines between PD patients and controls require the effect of pathology and time. Collectively, our results suggest that inflammatory mechanisms, specifically antigen presentation by microglia, in the substantia nigra have the potential to contribute to degeneration. Moreover, deviations in pro-inflammatory cytokines that occur in early disease stages are closely associated with α-syn burden within the SN. Importantly the combination of biofluid sampling and measurement of α-syn within the brain may represent a biomarker for early disease detection.
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Title: The role of parkin in maintaining proteasome activity following acute neurotoxic insult
Creator: Lansdell, Theresa A.
Date: 2017
Collection: Electronic Theses & Dissertations
Description: "The motor symptoms of Parkinson disease are primarily caused by the progressive degeneration of nigrostriatal dopamine neurons of the substantia nigra pars compacta. While these neurons are susceptible, tuberoinfundibular DA neurons are not affected. Exposure to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine (MPTP) results in a similar pattern of DA neuronal susceptibility. The recovery of tuberoinfundibular DA neurons is dependent upon the increased expression of parkin...
Show more"The motor symptoms of Parkinson disease are primarily caused by the progressive degeneration of nigrostriatal dopamine neurons of the substantia nigra pars compacta. While these neurons are susceptible, tuberoinfundibular DA neurons are not affected. Exposure to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine (MPTP) results in a similar pattern of DA neuronal susceptibility. The recovery of tuberoinfundibular DA neurons is dependent upon the increased expression of parkin following MPTP exposure. Parkin is an E3 ligase that contains a ubiquitin like domain that can bind to the 26S proteasome and directly enhance its activity. The purpose of this dissertation was to test the hypothesis that increased parkin expression is both necessary and sufficient to maintain proteasome activity following oxidative insult by MPTP. MPTP caused similar oxidative damage to proteins in regions containing axons terminals of nigrostiatal (striatum; ST) and tuberoinfundibular (median eminence; ME) DA neurons, however proteasome activity followed the differential pattern of parkin expression and was decreased in the ST and maintained in the ME. The ST of parkin knockout mice had decreased proteasome activity, accumulation of ubiquitinated TH, and increased oxidatively modified proteins, while these were not affected in the ME. Proteasome activity in the ME of parkin deficient mice was decreased following MPTP but oxidatively modified proteins were not changed in either the ME or ST. To determine if parkin up-regulation could rescue proteasome activity following exposure to MPTP, rAAV expressing Flag-tagged human parkin was injected into the substantia nigra containing cell bodies of nigrostriatal DA neurons and proteasome activity was measured 24 h post MPTP. Parkin overexpression in the substantia nigra increased basal proteasome activity and prevented MPTP-induced loss of proteasome activity in the ST. rAAV-mediated parkin expression resulted in activation of 26S proteasome activity that was due to an increase in the amount of assembled 26S proteasome. Furthermore, increased parkin expression resulted in the rescue of proteasome mediated turnover of ubiquitinated TH. Although parkin over-expression was not sufficient to rescue NSDA axon terminal DA stores following MPTP exposure, DA turnover was decreased. The data presented here reveal that parkin is necessary and sufficient for the maintenance of 26S proteasome activity in dopaminergic axon terminal regions following acute MPTP exposure. Over-expression of parkin may be beneficial in protecting nigrostriatal DA neurons from cytosolic DA related oxidative damage. In addition, the discovery of small molecules that positively modulate the 26S proteasome may have potential therapeutic applications in the treatment of Parkinson disease."--Pages ii-iii.
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