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Investigating the Role of Matrin-3 in Amyotrophic Lateral Sclerosis and Distal Myopathy

Ramesh, Nandini (2020) Investigating the Role of Matrin-3 in Amyotrophic Lateral Sclerosis and Distal Myopathy. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Matrin-3 (MATR3) is a ubiquitously expressed DNA/RNA-binding protein involved in regulating various aspects of RNA metabolism. MATR3-positive cytoplasmic inclusions have been identified in post-mortem brain tissues of amyotrophic lateral sclerosis (ALS) patients with G4C2 hexanucleotide repeat expansions in C9orf72 gene. Furthermore, pathogenic mutations in MATR3 have been discovered in patients with ALS and distal myopathy, suggesting multisystem proteinopathy involving degeneration of motor neurons and muscles. However, the underlying mechanisms of MATR3-mediated neuromuscular degeneration are still unknown.
Here, I developed Drosophila models expressing MATR3-WT and ALS/myopathy linked mutations that recapitulate key features of human disease including motor dysfunction and muscular atrophy. Using site-directed mutagenesis to investigate structure-function correlations, I found that MATR3 exerts toxicity through its RNA-binding domains. Through a genetic screen, I found that knocking down rump, Drosophila homolog of human hnRNPM, suppressed mutant MATR3 toxicity. In mammalian cells, MATR3 and hnRNPM colocalized together and showed RNA-mediated physical interaction, suggesting a role for hnRNPM in mediating mutant MATR3 toxicity. Additionally, I found that MATR3 genetically and functionally interacts with G4C2 repeat expansion in iPSC-derived motor neurons and Drosophila models of C9orf72-ALS through RNA-dependent mechanism(s).
Neuromuscular diseases impose a huge burden on public health with no effective therapies available. The work presented in this dissertation highlights the role of MATR3-mediated neuromuscular degeneration in ALS and myopathy, particularly through its RNA-binding functions; and identifies strong genetic modifiers that are potential candidates for future therapeutic intervention.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Ramesh, Nandininar64@pitt.edunar640000-0003-0860-2922
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairPandey, Udaiudai@pitt.eduudai
Committee MemberUrban, Zsolturbanz@pitt.eduurbanz
Committee MemberPadiath, Quasarqpadiath@pitt.eduqpadiath
Committee MemberDonnelly, Christopherchrisdonnelly@pitt.educhrisdonnelly
Committee MemberTodi,
Date: 30 July 2020
Date Type: Publication
Defense Date: 31 March 2020
Approval Date: 30 July 2020
Submission Date: 10 June 2020
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 149
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Amyotrophic lateral sclerosis Myopathy MATR3 C9ORF72
Date Deposited: 30 Jul 2020 16:16
Last Modified: 01 Jul 2022 05:17

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