Relationship Between TDP-43 Toxicity and Aggregation in Saccharomyces Cerevisiae

<p>Protein aggregation and inclusion body formation are hallmarks of neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis (ALS). These neurodegenerative diseases share a common pathology in that all include accumulation of insoluble protein aggregates in the brain. TAR-DNA-binding protein (TDP-43) is the major component found in the pathological inclusions of two of these diseases, ALS and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). This thesis focuses upon the biophysical basis for TDP-43 aggregation in <em>S. cerevisiae</em>. Current <em>in vitro</em> evidence indicates that TDP-43 is a natively dimeric protein and that binding to RNA inhibits aggregation. Corresponding genetic results in yeast in which specific components of the RNA-decay machinery have been knocked-out, indicate that the buildup of specific cellular RNAs is capable of counteracting TDP-43 aggregation and toxicity <em>in vivo</em>. This thesis provides evidence of separate pathologies of TDP-43 and TDP-43 mutants in <em>S. Cerevisiae</em>. This thesis also introduces preliminary data of the effect of <em>in vitro</em> synthesized RNA on TDP-43 toxicity.</p>

Name thesis:degree_name

M.S.

Level thesis:degree_level

Masters Thesis

Year dc:date.available

2018

Author dc:creator

• Aguilar, Martin Anthony

Contributors dc:contributor

• Erich G. Chapman, Ph.D.

• Amyotrophic lateral sclerosis
• Protein aggregation
• TDP-43
• TAR-DNA-binding protein
• Biochemistry, Biophysics, and Structural Biology
• Neuroscience and Neurobiology

Statement dc:rights

• <p>Copyright is held by the author. User is responsible for all copyright compliance.</p>

Language dc:language

en

Repository record dc:identifier

https://digitalcommons.du.edu/etd/1557

OAI identifier oai:identifier

oai:digitalcommons.du.edu:etd-2557