Date of Award

1-1-2018

Document Type

Thesis

Degree Name

M.S.

Department

Chemistry and Biochemistry

First Advisor

Erich G. Chapman, Ph.D.

Keywords

Amyotrophic lateral sclerosis, Protein aggregation, TDP-43, TAR-DNA-binding protein

Abstract

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 S. cerevisiae. Current in vitro 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 in vivo. This thesis provides evidence of separate pathologies of TDP-43 and TDP-43 mutants in S. Cerevisiae. This thesis also introduces preliminary data of the effect of in vitro synthesized RNA on TDP-43 toxicity.

Publication Statement

Copyright is held by the author. User is responsible for all copyright compliance.

Provenance

Received from ProQuest

Rights holder

Martin Anthony Aguilar

File size

62 p.

File format

application/pdf

Language

en

Discipline

Biochemistry

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