Year of Publication

2015

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Arts and Sciences

Department

Chemistry

First Advisor

Dr. D. Allan Butterfield

Abstract

Proteomics is the field of science in which proteins produced by an organism (the proteome) are identified. The level of a particular protein can vary with time and the influence of cellular stressors. The study of phosphoproteomics is vital because tyrosine, serine and threonine phosphorylation modulate protein structure and function and is a crucial regulator of cellular signaling pathways. Dysregulation of protein and phosphorylation levels has been reported in multiple neurodegenerative disorders including Parkinson disease (PD) and Alzheimer disease (AD).

PINK1 is a mitochondrial serine/threonine kinase that polices mitochondrial integrity. Mutations in this protein are associated with familial early-onset PD. PD is characterized by accumulated Lewy bodies, largely composed of aggregated alpha-synuclein, and progressive dopaminergic neuronal degeneration in the substantia nigra. In this dissertation study, proteomics identified differences in protein expression and protein phosphorylation levels in the brains of PINK1 knockout mice. The observed changes suggest that perturbed metabolism, diminished proteostasis, decreased neuronal plasticity, and aberrant cellular signaling are implicated in familial PD pathogenesis.

AD is characterized by senile plaques, neurofibrillary tangles and synapse loss. Previously, multiple AD brain proteins were reported from our laboratory as abnormally phosphorylated, indicating that deregulated phosphorylation may play a key role in AD pathogenesis. In this dissertation study, quantitative phosphoproteomic analyses were conducted on the inferior parietal lobule from three different clinical stages of AD, i.e., late-stage AD, amnestic mild cognitive impairment (MCI) and preclinical AD (PCAD). The differential phosphoproteins identified provide insights into underlying mechanisms promoting the preservation of memory in PCAD with expansive AD pathology, while uncovering early aberrant phosphorylation events in MCI that conceivably may be involved in the progressive cognitive decline leading to dementia.

Aging is a primary risk factor for development of neurodegenerative disorders, including AD and PD. The naked mole-rat (NMR), which can live for 32 years, is currently under investigation to gain insights into extending human lifespan and healthspan. In this dissertation research, age-related alterations of the brain proteome and phosphoproteome of the NMR were identified, revealing key proteins involved in neuronal plasticity, energy metabolism, autophagy, and the ubiquitin-proteasome system that may contribute to salubrious longevity.

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