Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that currently has no cure. We propose to investigate the roles of G-quadruplex (G4) structures and G4-assembling molecules in neurodegeneration and ALS pathogenesis. G4s are unique structures associated with multiple biological processes including genetic instability, transcriptional and post-transcriptional regulation of gene expression. We have previously identified novel stress response pathway, which is triggered by the ribonuclease angiogenin (ANG) by cleavage of cytoplasmic tRNA molecules to produce tRNA-derived stress-induced RNAs (tiRNAs). In turn, selective tiRNAs that are capable of assembling G4 structures (G4-tiRNAs) protect motor neurons from stress-induced injuries and death. This neuroprotection is achieved by the ability of G4-tiRNAs to reprogram gene expression on post-transcriptional level and by promotion of Stress Granules (SGs), pro- survival RNA granules implicated in the pathogenesis of ALS. Significantly, the disease-associated hexameric GGGGCC (G4C2) repeat expansion in the first intron of C9ORF72 gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (C9-FTD/ALS). Number of studies has shown that C9ORF72 transcripts with pathological G4C2 repeats (referred as RNA-G4C2 or rG4C2) significantly contribute to the development of C9-FTD/ALS. We and others have recently discovered that rG4C2 repeats assemble G4s. We hypothesize here that G4s play important regulatory roles, which are altered upon their amplification (such as observed during G4C2 expansion). Understanding of the physiological roles of G-quadruplexes in the context of neurodegeneration will provide important insights into the cellular and molecular mechanisms of ALS, and will evaluate novel G4- based therapeutic approaches for the treatment of motor neuron disease.

Public Health Relevance

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease caused by the progressive loss of motor neurons for which there is no cure. This project investigates the influence of specific RNA and DNA structures on the modulation of motor neuron survival as it relates to the pathogenesis of ALS. The outcome of this research will be the identification of targets for the development of a new class of neuroprotective drugs for use in patients with ALS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS094918-01
Application #
9016919
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Gubitz, Amelie
Project Start
2015-09-15
Project End
2017-08-31
Budget Start
2015-09-15
Budget End
2016-08-31
Support Year
1
Fiscal Year
2015
Total Cost
$266,188
Indirect Cost
$116,188
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Aulas, Anaïs; Lyons, Shawn M; Fay, Marta M et al. (2018) Nitric oxide triggers the assembly of ""type II"" stress granules linked to decreased cell viability. Cell Death Dis 9:1129
Lyons, Shawn M; Gudanis, Dorota; Coyne, Steven M et al. (2017) Identification of functional tetramolecular RNA G-quadruplexes derived from transfer RNAs. Nat Commun 8:1127
Aulas, Anaïs; Fay, Marta M; Lyons, Shawn M et al. (2017) Stress-specific differences in assembly and composition of stress granules and related foci. J Cell Sci 130:927-937
Lyons, Shawn M; Fay, Marta M; Akiyama, Yasutoshi et al. (2017) RNA biology of angiogenin: Current state and perspectives. RNA Biol 14:171-178
Aulas, Anaïs; Fay, Marta M; Szaflarski, Witold et al. (2017) Methods to Classify Cytoplasmic Foci as Mammalian Stress Granules. J Vis Exp :
Fay, Marta M; Lyons, Shawn M; Ivanov, Pavel (2017) RNA G-Quadruplexes in Biology: Principles and Molecular Mechanisms. J Mol Biol 429:2127-2147
Fay, Marta M; Anderson, Paul J; Ivanov, Pavel (2017) ALS/FTD-Associated C9ORF72 Repeat RNA Promotes Phase Transitions In Vitro and in Cells. Cell Rep 21:3573-3584
Kedersha, Nancy; Panas, Marc D; Achorn, Christopher A et al. (2016) G3BP-Caprin1-USP10 complexes mediate stress granule condensation and associate with 40S subunits. J Cell Biol 212:845-60
Szaflarski, Witold; Fay, Marta M; Kedersha, Nancy et al. (2016) Vinca alkaloid drugs promote stress-induced translational repression and stress granule formation. Oncotarget 7:30307-22
Panas, Marc D; Ivanov, Pavel; Anderson, Paul (2016) Mechanistic insights into mammalian stress granule dynamics. J Cell Biol 215:313-323

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