Zachary McEachin

BME PhD Defense Presentation

Date: June 19th, 2019

Time: 10:00 a.m.

Location:  Whitehead Memorial Research Building, Room 400 (Emory)

Committee members:

Gary J Bassell, PhD (Emory Cell Biology) (Advisor)

Jonathan Glass, MD (Emory Neurology)

Nicholas Hud, PhD (GaTech Chemistry)

Philip Santangelo, PhD (GaTech BME)

Thomas Kukar, PhD (Emory Pharmacology)

Title: Shared and unique disease mechanisms in hexanucleotide repeat expansion disorders

Abstract:  Pathological repeat expansions of short, genomic repeat sequences have been implicated in over 40 neurodevelopmental, neurodegenerative, or neuromuscular disorders.  Although the pathomechanisms associated with microsatellite repeat expansions are unclear, possible disease mechanisms that have been investigated include haploinsufficiency, toxic gain of function of the nucleotide repeats, and/or protein toxicity due to repeat associated non-ATG (RAN) translation.

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 Aim (3) 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.