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p(UG) RNA Quadruplexes as Nucleators of Stress Granules and Modulators of TDP-43 Pathology in ALS

Award Number: R16NS150184
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/10/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2030

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p(UG) RNA Quadruplexes as Nucleators of Stress Granules and Modulators of TDP-43 Pathology in ALS - Project Summary/Abstract Amyotrophic lateral sclerosis (ALS) is a clinically diverse neurodegenerative disease characterized by the nuclear depletion and cytoplasmic aggregation of the RNA-binding protein TDP-43. Under cellular stress, TDP-43 relocates to stress granules (SGs), which are dynamic, liquid-liquid phase-separated, membraneless RNA– protein condensates that typically dissolve upon stress resolution. However, persistent SGs can mature into pathological inclusions, a hallmark of ALS. While traditional models of SG assembly focused on proteins with low-complexity, intrinsically disordered regions, recent evidence highlights RNA structure as a critical driver of condensate nucleation and material state. Specifically, classical RNA G-quadruplexes can nucleate condensates and influence protein partitioning, demonstrating that distinct RNA folds, beyond mere sequence, govern SG dynamics. Our recent discovery of a non-canonical poly-UG (pUG) RNA quadruplex in C. elegans, formed on long UG tracts, revealed that UG repeats can adopt a stable quadruplex fold. Our preliminary work indicates that human UG12 tracts can also form pUG-like structures in vitro, further independent studies have presented that long UG tracts are the most highly enriched motif in SG-associated transcriptomes. Notably, TDP-43 exhibits high binding affinity for UG tracts of similar length, suggesting a convergence of RNA structure and protein recognition. This work is significant because it reframes SG biology as an RNA-structure-driven process, linking a specific, genetically encoded RNA fold to a defining pathological feature of ALS. This proposal investigates whether long UG tracts in human transcripts fold into pUG quadruplexes that nucleate SG assembly and recruit TDP-43, thereby promoting a shift from reversible, liquid-like condensates to the aggregated states characteristic of ALS. Establishing this link would define an RNA-structure code governing TDP-43 mislocalization into SGs, elucidating why specific transcripts are recurrently implicated in disease and providing a mechanistic bridge between transient stress responses and persistent pathology. Furthermore, this research will open novel RNA- targeted therapeutic avenues to restore proteostasis and RNA metabolism in ALS by identifying a clear mechanistic framework and tractable RNA targets for therapeutic modulation.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $745,000 )
2026	2026	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	B622 MAIN BUILDING FLR 6	SAN JUAN	PR	00935	SAN JUAN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/10/2026	NEW	$745,000
														Subtotal = $745,000

Grand Total All Awards = $745,000

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p(UG) RNA Quadruplexes as Nucleators of Stress Granules and Modulators of TDP-43 Pathology in ALS

Award Number: R16NS150184

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/10/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2030

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