Advisory Committee Chair
Laura A Volpicelli-Daley
Advisory Committee Members
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Lewy Body Diseases (LBDs) are a group of disorders characterized by intracellular inclusions of misfolded alpha-synuclein (α-synuclein). Of these, Parkinson’s Disease (PD) is the most common neurodegenerative movement disorder, and Dementia with Lewy Bodies (DLB) is the second most common neurodegenerative dementia. PD is characterized clinically by bradykinesia, resting tremor, rigidity, and postural instability. In addition, up to 80% of patients eventually develop dementia, termed Parkinson’s Disease Dementia (PDD). DLB is characterized by onset of dementia before or concurrently with parkinsonism. Currently, no disease-modifying therapies exist for either of these diseases. Lewy pathology is found in regions important for cognition in both PDD and DLB, and may correlate with cognitive decline. This thesis shows Lewy-like pathology induced by α-synuclein fibrils exists in excitatory neurons in the cortex and amygdala of mice. Alpha-synuclein fibrils are able to recruit endogenous α-synuclein to misfold and aggregate, modeling sporadic LBDs without the need for transgenic lines. Mice with these inclusions have non-motor behavioral deficits associated with the brain regions with abundant Lewy-like pathology. In addition to α-synuclein, the microtubule binding protein tau has been implicated in LBDs, and its role is unknown. Tau binds to α-synuclein and has been shown to increase its propensity to aggregate. Reducing endogenous tau rescues cognitive deficits and premature mortality in models of Alzheimer’s Disease, and shows benefit in a transgenic α-synuclein mouse line. The work here shows tau reduction does not protect against α-synuclein fibril-induced Lewy-like inclusions in the dorsomedial prefrontal cortex, basolateral amygdala, hippocampus, or substantia nigra pars compacta. Additionally, tau reduction did not protect against dopaminergic neurodegeneration. In primary neuronal culture, tau did not affect internalization of α-synuclein fibrils. Interestingly, tau reduction led to a substantial decrease in mobile fibril puncta traveling towards the cell body within an hour of exposure. This, when combined with the in vivo results from 6 months after injection, suggest tau may affect transport of fibrillary α-synuclein but not prevent recruitment of endogenous α-synuclein. Alternatively, tau reduction may cause an initial slowing of Lewy-like inclusion formation that is not seen at late time points.
Stoyka, Lindsay, "Role Of Endogenous Tau In Lewy-Like Pathology" (2020). All ETDs from UAB. 928.