Date of Award
Spring 2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Genetics
First Advisor
Lim, Janghoo
Abstract
Spinocerebellar ataxia type 1 (SCA1) is a rare, dominantly inherited monogenic neurodegenerative disease that primarily affects the Purkinje cells (PCs) of the cerebellum. Our lab utilizes SCA1 as a model to unravel the complexity that is neurodegeneration. Neurodegeneration has long been a challenge due to the interactions of multiple cell types, various disease-causing genes, and degeneration beyond a single brain region. We utilized the SCA1 82Q B05 transgenic model (B05) which expresses the disease-causing gene, ATAXIN-1 (ATXN1), only in the PCs of the cerebellum. This mouse model recapitulates the disease phenotypes seen in human patients and allows us to investigate whether mouse genetic background can modify the pathogenesis of SCA1, and whether these findings can be applied to the field of neurodegeneration as a whole. ` In the first chapter, I provide an in-depth introduction of SCA1 phenotype, affected brain regions, and highlight the various mouse models that have been generated to study SCA1. I conclude that there have been differences in the expression of motor loss in these mouse models including within models, and that the difference may lie in the genetic background of these mice. In the second chapter, I propose the generation of a new SCA1 B05 mouse model which retains the disease causing ATXN1 gene while also having a genetically distinct background. Here I characterize the expression of Ataxin-1 at both the RNA and protein level at four distinct time-points (5-, 12-, 20-, and 52-weeks of age) and show that they are similar and can be an apt comparison in the chapters that follow. In the third chapter, I perform an in-depth analysis of the motor behavior over time using various methods that are standard in the field. I further show the results from immunofluorescent imaging (IF) of the cerebellum of SCA1 mice over four time-points to measure how much neurodegeneration has occurred at each time-point and over time. The motor loss and neurodegenerative phenotype of these SCA1 backgrounds are compared and the similarities and differences of the pathogenic findings are further addressed through an analysis of the molecular changes that occur in SCA1. I conclude that genetic background can affect SCA1 pathogenesis in both motor loss and neurodegeneration. In the fourth chapter, I describe my investigations of the molecular changes that are occurring in SCA1 pathogenesis. We performed a traditional analysis of differentially expressed genes (DEGs) as well as an analysis of misregulated alternatively spliced (mAS) RNA. We were the first to show that mAS events occur in SCA1. We observed shared transcriptomic changes in ion channel genes to be the most affected across time-points and backgrounds in both DEG and mAS data sets. Analysis of the unique DEGs helped to show the molecular pathways which may be causative of neurodegeneration of the molecular layer in the FVB background and protective in the F1 background. Analysis of unique SE mAS events showed that misregulation of protein localization occurred at the same time-points when motor loss is first observed in each background. Whether misregulation of protein localization proteins is causative for motor loss should be further investigated. Taken together, these data proves that mouse genetic background can modify SCA1 pathogenesis in both motor function and neurodegeneration phenotypes. Analysis of the molecular changes, both DEGs and mAS events, are crucial to understand how and why SCA1 pathogenesis is modified due to mouse genetic background. Both the shared and unique transcriptionally affected pathways are important in understanding which pathways are involved in the progressive degeneration seen on both backgrounds, and which pathways are involved in the modification of the expression of neurodegeneration on each genetic background. Modification of disease pathology due to changes in genetic background is not limited to SCA1, and therefore the role of mouse genetic background should be investigated in other neurodegenerative genetic diseases.
Recommended Citation
Olmos, Victor Hipolito, "Genetic background’s influence on the pathogenesis of Spinocerebellar Ataxia Type 1 (SCA1)" (2024). Yale Graduate School of Arts and Sciences Dissertations. 1417.
https://elischolar.library.yale.edu/gsas_dissertations/1417
