Interdisciplinary Graduate Program
First Thesis Advisor
John E. Landers, PhD
Amyotrophic Lateral Sclerosis, Drosophila, Motor Neurons, Profilins, PFN1 Mutations
Dissertations, UMMS; Amyotrophic Lateral Sclerosis; Drosophila; Motor Neurons; Profilins; Mutation
Amyotrophic lateral sclerosis (ALS) is a progressive adult neurodegenerative disease that causes death of both upper and lower motor neurons. Approximately 90 percent of ALS cases are sporadic (SALS), and 10 percent are inherited (FALS). Mutations in the PFN1 gene have been identified as causative for one percent of FALS. PFN1 is a small actin-binding protein that promotes actin polymerization, but how ALS-linked PFN1 mutations affect its cognate functions or acquire gain-of-function toxicity remains largely unknown.
To elucidate the contribution of ALS-linked PFN1 mutations to neurodegeneration, we have characterized these mutants in both mammalian cultured cells and Drosophila models. In mammalian neuronal cells, we demonstrate that ALS-linked PFN1 mutants form ubiquitinated aggregates and alter neuronal morphology. We also show that ALS-linked PFN1 mutants have partial loss-of-function effects on actin polymerization in growth cones of mouse primary motor neurons and larval neuromuscular junctions (NMJ) in Drosophila. In Drosophila, we also observe that PFN1 level influences integrity of adult motor neurons, as demonstrated by locomotion, lifespan, and leg NMJ morphology.
In sum, the work presented in this dissertation has shed light on PFN1- linked ALS pathogenesis by demonstrating a loss-of-function mechanism. We have also developed a Drosophila PFN1 model that will serve as a valuable tool to further uncover PFN1-associated cellular pathways that mediate motor neuron functions.
Wu, C. Functional Characterization of Novel PFN1 Mutations Causative for Familial Amyotrophic Lateral Sclerosis: A Dissertation. (2015). University of Massachusetts Medical School. GSBS Dissertations and Theses. Paper 815. DOI: 10.13028/M2WS38. http://escholarship.umassmed.edu/gsbs_diss/815
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