Title:
Mechanistic insight into disease pathogenesis of hexanucleotide repeat expansion disorders
Mechanistic insight into disease pathogenesis of hexanucleotide repeat expansion disorders
Author(s)
McEachin, Zachary T.
Advisor(s)
Bassell, Gary J.
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Abstract
In 2011, two highly related hexanucleotide repeat expansions (HRE) were discovered as the causes of two different diseases – an intronic G4C2 HRE in the C9ORF72 gene locus represents the most prevalent genetic cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), referred to as c9FTD/ALS, and a TG3C2 HRE in the first intron of NOP56 gene was independently identified as the genetic cause for a clinically disparate disease, Spinocerebellar Ataxia type 36 (SCA36). The overall aim of this proposal is to elucidate the molecular mechanisms by which hexanucleotide repeat expansions result in neurodegenerative disease, and to identify which mechanisms are responsible for the disease-specific pattern of neuronal degeneration and loss in these disorders. Aim (1) will determine whether these intronic hexanucleotide repeats are unconventionally translated into dipeptide repeats, Aim (2) will identify and compare disease specific RNA-protein interactions, and lastly we will use next generation sequencing to elucidate shared and distinct dysregulated pathways in these two disorders. We hypothesize that a comprehensive and comparative analysis using c9FTD/ALS and SCA36 patient samples will provide us with a unique opportunity to gain a thorough understanding of the common and disease-specific pathomechanisms of these devastating disorders, for which there are presently no available cures or effective treatments.
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Date Issued
2019-07-30
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Text
Resource Subtype
Dissertation