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Understanding the Sequence and Structural Determinants of Phase Behavior of ALS-Causing Proteins

Award Number: R01NS121114
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: 02/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Understanding the Sequence and Structural Determinants of Phase Behavior of ALS-Causing Proteins - SUMMARY Stress granules (SGs) are important players to the pathogenesis of a spectrum of neurodegenerative diseases that include Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS) and frontotemporal dementia (FTD). SGs form in response to cellular stresses, and their job is to protect cells from the deleterious consequences of stress, which include the release of untranslated naked unfolded mRNAs (nuRNAs) into cells. SGs form via reversible co-phase separation of G3BP and nuRNA molecules. SGs also recruit RNA binding proteins (RBPs) with RNA recognition motifs (RRMs) and prion-like low complexity domains (PLCDs) from the cytosol and nucleus. A key unanswered question is how do RBPs contribute to the capacity of SGs to buffer against nuRNAs? Answering this question, which is the focus of AIM 1, is central to enhancing the buffering capacity of SGs, which will likely be a productive way to intervene therapeutically in AD, ALS, and FTD. We will test the hypothesis that in addition to adding RNA-processing capabilities via their RRMs, proteins with RRMs and PLCDs contribute homotypic and heterotypic interactions to enhance the driving forces for phase separation of SGs and SG-like condensates. Paradoxically, by using RBPs to assemble SGs, cells seem to create an inherent risk for themselves. We recently found that the threshold concentration for amyloid fibril formation of an archetypal SG-associated RBP is lower than the threshold RBP concentration for condensation that drives SG assembly. Disease-causing mutations further increase the condensation threshold of RBPs, while lowering their threshold concentration for fibril formation. This gap between threshold concentrations creates a toxic scenario whereby amyloid formation of RBPs can become an inevitable thermodynamic consequence of SG assembly. Thus, the second crucial and as yet unanswered question is how do cells form functional SGs while avoiding fibril formation of their RBPs? Answering this question through rigorous biophysical approaches that combine computations, theory, and experiments will be the focus of AIM 2. We will test the hypothesis that the material properties of SG-like condensates, specifically their viscoelasticity along with the interfacial densities of sites that contribute to heterogenous nucleation will combine with thermodynamic metastability to determine the sink potentials of condensates. If the hypothesis is valid, then the findings from our work will represent a paradigm shift in our thinking about the roles of SGs in pathology. The progress we make will be foundational and important for determining strategies towards therapeutic treatments of devastating and currently untreatable neurodegenerative diseases that include AD, ALS, and FTD.


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 = $697,992 )
2026	2026	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	6	8/7/2026	COMPETING CONTINUATION	$697,992
2026	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	7/30/2026	NON-COMPETING CONTINUATION	$0
2026	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $697,992

Issue Date FY: 2025 ( Subtotal = $623,969 )
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/20/2025	NON-COMPETING CONTINUATION	$561,572
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	8/5/2025	NON-COMPETING CONTINUATION	$62,397
														Subtotal = $623,969

Issue Date FY: 2024 ( Subtotal = $605,252 )
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/18/2024	NON-COMPETING CONTINUATION	$561,572
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/10/2024	NON-COMPETING CONTINUATION	$43,680
														Subtotal = $605,252

Issue Date FY: 2023 ( Subtotal = $623,969 )
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/29/2022	NON-COMPETING CONTINUATION	$561,572
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	2/27/2023	NON-COMPETING CONTINUATION	$62,397
														Subtotal = $623,969

Issue Date FY: 2022 ( Subtotal = $623,969 )
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	6/24/2022	NON-COMPETING CONTINUATION	$62,399
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/31/2022	NON-COMPETING CONTINUATION	$561,570
														Subtotal = $623,969

Issue Date FY: 2021 ( Subtotal = $643,844 )
2021	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/28/2021	NEW	$643,844
														Subtotal = $643,844

Grand Total All Awards = $3,818,995

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Understanding the Sequence and Structural Determinants of Phase Behavior of ALS-Causing Proteins

Award Number: R01NS121114

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: 02/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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