Date of Award

1-1-2018

Document Type

Thesis

Degree Name

M.S.

Department

Chemistry and Biochemistry

First Advisor

Erich G. Chapman

Keywords

Amyotrophic lateral sclerosis, Protein Aggregation, TDP-43

Abstract

Protein aggregation and inclusion body formation are hallmarks of neurodegenerative diseases such as Alzheimerâ??s, Parkinsonâ??s, Huntingtonâ??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.

Provenance

Recieved from ProQuest

Rights holder

Martin Anthony Aguilar

File size

62 p.

File format

application/pdf

Language

en

Discipline

Biochemistry

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