Date of Award

2021

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Biological Sciences

First Advisor

Simon Moller

Second Advisor

Daniella Howarth

Third Advisor

Yong Yu

Abstract

Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder predominately affecting the aging population. It is the second most common neurodegenerative disorder after Alzheimer’s disease (AD) affecting over 1 million individuals in the US alone. Recent studies have tried to understand the exact nature in which healthy neurons transition to a degenerative state in PD. There are a multitude of combinatory factors that can lead to the development of PD including environmental factors, genetic factors, and aging. The majority of PD cases are sporadic in nature, however familial cases account for 5-10% of total PD cases world-wide. The hallmark feature of PD is the formation of Lewy bodies, abnormal protein aggregates enriched in the protein -synuclein (a-syn) in dopaminergic neurons of the substantia nigra. These aggregates affect the overall protein homeostasis (proteostasis) in neurons causing deleterious effects. The lack of accurate diagnostic biomarkers clearly represents a challenge for PD patients and their caregivers. It has become increasingly apparent that microRNAs (miRNA), key regulators of gene expression, are involved in numerous disease processes including PD. We investigated miR-335-5p and miR-3613-3p, two microRNAs previously reported by our laboratory, to be significantly up-regulated in serum samples of PD patients as compared to healthy age-matched controls. We also corroborated those findings when we extracted RNA from frontal cortex tissue of PD patients and age-matched controls finding that miR-335-5p, miR-3613-3p, and miR-6865-3p were all significantly upregulated in patients with PD. Using mass spectrometry and in silico prediction methods we identified a number of potential protein targets for both miR-335-5p and miR-3613-3p. Using several molecular approaches, we found that three proteins involved in PD pathogenesis are regulated by miR-335-5p and miR-3613-3p, respectively. Ataxin-3 (ATXN3), BCL2 Associated athanogene 5 (BAG5), and Autophagy related 5 (ATG5) are all proteins targeted and regulated by both miR-335-5p and miR-3613-3p. miR-335-5p and miR-3613-3p have not previously been characterized for their potential biological roles with respect to neurodegeneration or neuroprotection. In this study we further dissect the neuroprotective role of both miR-335-5p and miR-3613-3p in cells induced with stress. Our results significantly contribute to our understanding of PD and the contributing factors to neurodegeneration.

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