Evaluating Proteinopathy and Consequences for Behavior in Animal Models of Human Neurodegenerative Disease

Abstract

Neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD) and Parkinson’s Disease (PD) are devastating and incurable conditions associated with human aging that are rapidly growing in incidence and global economic burden. While these diseases of the central nervous system are complex, heterogeneous and multi-factorial in humans, experimental animal models based on the most common pathological predictors provide a framework for elucidating the cellular and molecular mechanisms leading to the progressive deterioration of behavior that largely characterizes these afflictions. Chapter 1 of this dissertation summarizes current literature outlining the characterization and pathophysiology of ALS, FTD and PD. Chapter 2 summarizes my contribution to novel work modeling FTD in fruit flies (Drosophila melanogaster) based on TDP-43 proteinopathy in mushroom body (MB) neurons. This work demonstrates a progressive thinning of MB lobes with resulting deficits in working memory, sleep and lifespan, and uncovers novel RNA targets of TDP-43 proteinopathy in MB neurons that are both unique and shared with targets identified in motor neurons within a fly model of ALS. Chapter 3 describes my most recent work in zebra finch songbirds evaluating the regional and subcellular distribution of alpha-synuclein (αsyn) neuropathy in the basal ganglia and the resulting effects on song behavior. This work establishes a novel tool, the Border Expression Ratio, for measuring locality and severity of αsyn neuropathy, revealing a positive correlation between right hemisphere pathology and a reduction in the variation of harmonic syllable duration. This work also revealed the detection of pSer129, a marker for pathologically aggregated αsyn typically enriched in Lewy bodies common to PD. Chapter 4 discusses the convergence of pathologies across neurodegenerative diseases, the limitations of these models and suggestions for future studies.