A Modulatory Role for Alpha-Synuclein During Ectopic Neuronal Cell Cycle Re-Entry: Implications for Alzheimer's Disease and Parkinson's Disease
Khan, Shahzad, Department of Neuroscience, University of Virginia
Bloom, George, As-Biology, University of Virginia
Alpha-synuclein (αSyn) is enriched in presynaptic terminals of neurons where it maintains synaptic vesicle stores, promotes SNARE complex assembly, and regulates exocytosis. Under diseased conditions such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), soluble αSyn is associated with neurodegeneration. However, the precise mechanism(s) by which αSyn causes neuron loss are ill-defined. The purpose of this thesis was to investigate the functional role of αSyn during the induction of ectopic neuronal cell cycle re-entry (CCR), a prelude to neuron loss in AD. The results show that αSyn bi-directionally modulates the Amyloid-β oligomer-induced increase in cyclin D1 in primary neuronal cultures and also ameliorates neuronal cyclin D1 expression in mutant Amyloid Precursor Protein (APPJ20) animals. Moreover, αSyn modulation of CCR directly correlated to the increase production of OC- and A11-positive Amyloid-β assemblies. Furthermore, MC1-tau in primary neurons and transgenic mice were found to be bi-directionally modulated by αSyn. Upon overexpression of human αSyn in APPJ20 mice, a decline in Barnes maze performance was observed when compared to the APPJ20 parental strain. By contrast, genetic ablation of αSyn in APPJ20 restored Barnes maze performance to comparative levels found in non-transgenic mice. Although this thesis will discuss limitations of the results and potential future directions, our conclusions underscore a central role for αSyn in AD pathogenesis and offer novel insight into αSyn neurotoxicity.
PHD (Doctor of Philosophy)
Neurodegeneration, Alzheimer's disease, Parkinson's disease, Tau, Alpha-Synuclein, Amyloid-Beta, Neuronal Cell Cycle Re-Entry
National Institutes of HealthAlzheimer's AssociationOwens Family FoundationCure Alzheimer's FundUniversity of Virginia's President's Fund for ExcellenceWeb and Tate WilsonVirginia Chapter of the Ladies Auxiliary of the Fraternal Order of Eagles
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