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Parkinson’s disease (PD) is among the most devastating neurodegenerative disorders, and affects 1% of the global population above the age of 60. Several mechanisms have been proposed to explain the dopamine degeneration exhibited in PD: mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. Inaccurate diagnosis is one of the greatest challenges to treatment of PD. Currently, there is no standard diagnostic test for PD. Neurotrophic factors (NTF) are secreted proteins that promote survival and maintenance of neurons during development. The loss of NTFs for specific neuronal populations could confer susceptibility to various neurodegenerative disorders. Cerebral dopamine neurotrophic factor (CDNF) is a novel NTF selective for dopamine neurons. CDNF has demonstrated profound neuroprotective and neurorestorative effects on dopamine neurons in well established animal models of PD. Presently, there are no studies examining endogenous levels of CDNF in PD models or clinical populations of PD, prompting the present study. Findings will bring insight into the neurobiological mechanisms underlying neurodegeneration in PD. This study has determined that CDNF protein and mRNA expression is not altered following 6-OHDA lesioning, suggesting a compensatory mechanism of CDNF in response to injury. We have also determined that CDNF mRNA expression declines with age, which could confer susceptibility to developing neurodegenerative diseases such as PD. In clinical populations of PD, platelets showed a significant increase in CDNF mRNA expression that was not seen in lymphocytes or whole blood. This suggests a role of CDNF in PD, specifically for platelets; however, it is important to delineate whether this increase is the result of treatment. Incidentally, we found that CDNF mRNA expression is significantly reduced following stroke. Together, these results stress the importance of CDNF in disorders stemming from ER stress. Future studies should examine the role of CDNF in preclinical models of stroke, as well as knockout models of PD. / Thesis / Master of Science (MSc)

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Parkinson's Disease (PD) is the second most common neurodegenerative condition in humans, after Alzheimer's disease. It can be observed in all races and both genders, in the United States and worldwide. However, disparities in disease progression and manifestation exist between races and sexes. In addition, treatment options and overall health, impacted by insurance type, may affect a PD patient's disease state. The purpose of this study is to contribute to the background demographic information of PD patients, particularly as pertaining to insurance classification, which has not yet been addressed in the literature. The Hoehn and Yahr (H&Y) scores of patients both ON and OFF medication, a method of ranking and analyzing disease severity in Parkinson's patients, were analyzed in this study. The hypothesis is that the H&Y scores are impacted by race, gender, and insurance status. A univariate analysis of each variable was performed, the Student's t-test was used for gender and insurance status and a One-way ANOVA for race. A multivariate regression model analysis was then run for the primary outcomes and included all the variables and known confounders. A secondary analysis of disease complications utilizing Chi-square tests and logistic regression was also performed. Gender and insurance status did not differ significantly in H&Y scores. Black or African patients had a significantly increased PD progression as compared to Caucasian patients. Males and females differed significantly with regard to several disease complications. Subjects with public insurance also exhibited greater odds of some disease complications as compared to subjects with private insurance. In agreement with the literature, black PD patients exhibited a greater disease progression as compared to white PD patients. However, the reason for this has not yet been adequately addressed. In addition, more studies are needed to analyze other racial groups that were too small to appropriately address in this study. Despite a lack of difference in H&Y scores, PD is observed to be manifested differently between genders (disease complications), also in agreement with the literature. More studies are required to discover the reason for this disparity. Insurance classification does not impact H&Y scores. However, more studies are required to address whether this is maintained with a more sensitive outcome measure, such as the UPDRS. In addition, some complications differ between insurance categories, implying a disparity in treatment options and therapies.

In addition to the classic motor symptoms, Parkinson’s disease (PD) causes a variety of non-motor symptoms that compromise quality of life and daily functioning. Anxiety, in particular, is prevalent and debilitating, but under-studied and under-treated. There is urgent need to understand the relation of anxiety to other non-motor symptoms, and to develop evidence-based treatments. Cognitive-behavioral therapy (CBT) and aerobic and resistance exercise are promising non-pharmacological treatment strategies for anxiety in PD, with potential to simultaneously reduce additional PD symptoms. Study 1 assessed a large sample of non-demented individuals with mild to moderate PD (N=77) and examined the relation between self-reported anxiety (Beck Anxiety Inventory [BAI]) and cognition with a focus on executive function and attention (Trail Making, Verbal Fluency, Digit Span). The majority of participants reported subclinical symptoms of anxiety (BAI ≤18). Higher anxiety correlated with poorer set-shifting, as well as with more advanced disease stage and severity. Study 2 implemented a single-case experimental design to evaluate the utility and feasibility of a 12-week cognitive-behavioral intervention for individuals with PD who also met criteria for a DSM-5 anxiety disorder (N=9). Weekly therapy sessions were conducted in-person (N=5) or via secure videoconferencing (N=4). At post-treatment, five participants reported significant reductions in anxiety and two additional participants reported significant reductions in comorbid depression. Most improvements were maintained at 6-week follow-up. Effects of CBT on secondary outcome measures (e.g., cognition, motor symptoms, sleep) varied widely across participants. Adherence and retention were high, as was satisfaction with treatment. Study 3 reviewed the effects of aerobic and resistance exercise on disturbances of mood, cognition, and sleep in PD and healthy adults. The literature supports aerobic and resistance exercise as feasible and promising adjunct treatments for mood, cognition, and sleep in PD, contingent upon additional exercise research that systematically targets non-motor symptom outcomes. Together these studies show that even subclinical anxiety is associated with cognitive disturbance in mild-moderate PD, and provide preliminary evidence for the effectiveness of CBT (in-person and internet-delivered), as well as aerobic and resistance exercise, as encouraging and viable treatments for anxiety in this disorder. / 2019-09-29T00:00:00Z

<p>Parkinson’s disease (PD) is an age-related neurodegenerative disorder characterized by pathological features that include the selective loss of dopaminergic (DA) neurons in the substantia nigra (SN) region of the midbrain and the presence of intraneuronal Lewy body and Lewy neurite inclusions primarily comprised of fibrillar forms of the pre-synaptic protein alpha-synuclein (aSyn).  aSyn aggregation has been implicated as a critical event in PD pathogenesis, and mutant forms of aSyn are associated with familial, early-onset forms of the disease. PD presents clinically as a movement disorder through appearance of its cardinal motor symptoms of bradykinesia, rigidity, postural instability, and resting tremor. However, upon manifestation of these clinical symptoms, over 50% of the DA nigral neurons have been lost, suggesting that PD neuropathology likely begins 10-15 years prior to the clinical onset. Current PD treatment is focused on symptomatic therapy through dopamine replacement strategies, and there are currently no medications available to prevent or slow disease progression. </p> <p>A major hurdle to developing disease-modifying therapies for PD is a lack of knowledge of the molecular phenomena responsible for the death of DA neurons in the SN. Multiple cellular pathways that are dysregulated in PD include protein clearance systems and oxidative stress responses. Changes in these systems by environmental or genetic perturbations cause increased aSyn aggregation, which in turn leads to increased oxidative and proteasomal stress, thereby generating a vicious cycle culminating in the death of nigral DA neurons. Therefore, strategies to activate these protective pathways have the potential to reduce aSyn aggregation and halt neurodegeneration. One such mechanism is through the activation of the stress-induced transcription factor, Nfe2L1. Nfe2L1 is a cap ‘n’ collar basic leucine zipper (CNC-bZIP) transcription factor that forms heterodimers with small Maf proteins. In turn, the heterodimers bind to antioxidant response element (ARE) sequences in the promoter regions of cytoprotective genes, such as genes encoding proteasome subunits and proteins involved in the glutathione synthesis pathway. In the studies summarized in Chapter 2, we have characterized a pre-clinical <em>in vivo</em> model of PD involving aSyn overexpression in rat SN and used this model to investigate whether Nfe2L1 co-expression could alleviate aSyn neurotoxicity by reducing cytosolic aSyn levels via proteasome activation. Using unbiased stereology to determine nigral DA neuron cell counts, we found that Nfe2L1 may have a protective effect against aSyn-mediated nigral DA neurodegeneration. Surprisingly, we observed no increase in proteasome subunit expression through quantitative PCR or immunoblotting. However, by using a single-neuron analysis approach, we observed a significant increase in PSMC1 subunit expression, suggesting that Nfe2L1 expression could indeed lead to an upregulation of proteasome subunits and an increase in proteasome function. Future experiments will be aimed at determining whether Nfe2L1 expression results in an increase in proteasome activity, an enhancement of aSyn degradation, and a decrease in the burden of proteinase K-resistant (Lewy-like) aSyn aggregates in rat SN. </p> <p>The ability to detect PD in the pre-symptomatic stage is necessary for the development of novel therapies to enable treatment prior to irreversible neuronal loss. Biomarkers with high sensitivity and specificity are critical for early PD detection. aSyn levels have been measured in human biofluids, such as blood and CSF, as a potential biomarker for PD diagnosis and for monitoring disease progression. aSyn can undergo a number of post-translational modifications (PTMs), and a particular form of the protein phosphorylated at serine 129 (pS129-aSyn) is enriched in Lewy bodies, making it an attractive candidate for biomarker studies. Although there are several antibodies targeting pS129, little is known about the influence of PTMs close to pS129 on the antibodies’ affinity for the pS129 epitope, or how these neighboring PTMs could affect assays developed to quantify pS129-aSyn in biofluids. In the studies summarized in Chapter 3, we characterized the impact of PTMs near pS129 on the affinity of currently available pS129-aSyn antibodies for their target antigen using biolayer interferometry (BLI). BLI analysis of the D1R1R pS129-aSyn antibody (Cell Signaling Technology) revealed that tyrosine phosphorylation or nitration at Y133 greatly reduced antibody affinity. In contrast, the MJF-R13 pS129-aSyn antibody (Abcam) was found to have reduced affinity for peptide targets nitrated or phosphorylated on Y125 or phosphorylated on Y133. </p> <p>While aSyn is typically investigated as it relates to PD and other neurodegenerative disorders, recently reported evidence suggests that aSyn downregulation could be linked to an increased risk of neurodevelopmental disorders such as autism spectrum disorder (ASD).  ASD is a complex neurodevelopmental disorder that presents with characteristic behavioral symptoms of social and communication impairments and restricted, repetitive behaviors. Diagnosis of ASD is based on the presentation of these behavioral symptoms, typically appearing at ~12 months of age, yet individuals don’t receive a diagnosis until the age of five. Early identification and early treatment are regarded as two of the most important factors for improving patient outcomes. SNCA gene deletions and loss-of-function duplications have been found in individuals with intellectual disability, developmental delay, and/or ASD, leading to the idea that reduced aSyn expression may be a biomarker for early ASD diagnosis and may play a role in ASD neuronal dysfunction. In the studies summarized in Chapter 4, we evaluated salivary aSyn as a potential biomarker for early ASD diagnosis and examined SNCA-/- iPSC-derived cortical neurons for indications of ASD-related neuronal anomalies. Our preliminary results suggest that salivary aSyn is reduced in individuals with neurodevelopmental disorders such as ASD and Fragile X Syndrome (FXS), a result consistent with findings of reduced aSyn in serum and plasma from ASD individuals. Furthermore, SNCA-/- iPSC-derived cortical neurons depleted of aSyn expression had increased soma size, a characteristic of iPSC-derived cortical neurons with ASD-associated mutations in the genes encoding MECP2 and TSC1/2 These results suggest that SNCA gene disruptions play a role in ASD-related neuronal anomalies and dysfunction. </p> <p>Overall, the results presented in this thesis support a role for targeting aSyn protein expression in neurodegenerative and neurodevelopmental disorders, and they underscore the importance of designing aSyn biomarker immunoassays that faithfully report on each of these syndromes. Our data suggesting that Nfe2L1 could protect against nigral neurodegeneration by stimulating proteasome-mediated aSyn clearance imply that strategies to increase Nfe2L1-dependent transcriptional activity (e.g., using small molecule activators or gene therapy) could ameliorate pathological aspects of PD. The results presented here also highlight the need for sensitive and specific biomarker assays targeting multiple aSyn proteoforms, and they suggest that aSyn could be a viable biomarker for early ASD diagnosis. Finally, our findings provide the first evidence that aSyn down-regulation contributes to neuronal anomalies associated with ASD, in turn suggesting that strategies to increase cytosolic aSyn by preventing its degradation or through gene therapy could potentially mitigate ASD neuronal dysfunction. </p>

Parkinson’s Disease (PD), the second most common neurodegenerative disease worldwide, pathologically presents with the inclusion of Lewy bodies and dopaminergic cell loss in the brain. Lewy bodies are composed of aggregated a-synuclein protein, and although essential to our understanding of PD, not much is known about the native, pre-synaptic state of a-synuclein (a-syn). Due to its mostly synaptic local, immunostaining results in diffuse signal, ultimately providing little insight into the types of a-syn-resident cells. As a result, insight into a-syn expression driven cellular vulnerability has been difficult to ascertain. Using a knockin mouse model that localizes a-syn to the nucleus of cells by insertion of a nuclear localization signal into the a-syn gene locus (SncaNLS), we overcome visualization issues and map out the topography and cells-of-origin of a-syn in mice. I performed immunohistochemistry on SncaNLS mouse tissue to map out the endogenous distribution of a-synuclein in the brain. Using ilastik machine learning analysis, I determined regions with high a-syn expression, which were subsequently co- stained with cell-type specific markers to gain further topographical granularity. a-syn showed high expression in the olfactory bulb, hippocampus, cerebral cortex, substantia nigra and cerebellum. Within these structures, there was a high level of expression of a-syn in granule cells, pyramidal cells, mitral cells, and dopaminergic neurons. Taken together, the SncaNLS mouse serves as a tool to define an atlas of a-syn topography, potentially providing insight into cellular vulnerability in PD.

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