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Understanding and Manipulating the Degradation of the C9orf72 Repeat Expansion RNA

Award Number: F30AG076323
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/01/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Understanding and Manipulating the Degradation of the C9orf72 Repeat Expansion RNA - PROJECT SUMMARY/ABSTRACT Understanding and Manipulating the Degradation of the C9orf72 Repeat Expansion RNA Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive, fatal neurodegenerative diseases. The most common cause of hereditary ALS and FTD is an expansion of the G4C2 sequence in an intron of the C9orf72 gene (c9ALS/FTD). A hallmark pathologic feature of c9ALS/FTD is the presence of repeat expansion RNA foci in neuronal nuclei, which is unusual because introns are usually degraded too rapidly to be easily detected. The accumulating G4C2 repeat expansion RNA is thought to contribute to c9ALS/FTD disease development in two ways: it can sequester RNA-binding proteins and disrupt their function, and it can be exported into the cytoplasm for translation into toxic dipeptide repeat proteins. The persistence of the repeat expansion RNA suggests that it forms a stable RNA structure that resists the normal intron degradation machinery. However, eukaryotic cells contain specific mechanisms for the degradation of RNAs with strong secondary structures. Such RNAs are post-transcriptionally modified with 3' oligo-uridine or oligo-adenosine tails that then recruit processive 3' to 5' exonucleases to degrade the RNA. I hypothesize that the C9orf72 repeat RNA is a poor substrate for normal intronic degradation pathways and that 3’ end tailing determines its rate of decay. To test this, the goal of this proposal is two-fold: I will determine the composition of the repeat expansion RNA that accumulates into nuclear foci to learn where intronic degradation is stalling (Aim 1), and I will examine the changes to the sequence and levels of the G4C2 repeat expansion RNA in response to perturbations to 3’ end tailing, tail removal, and RNA degradation (Aim 2). Taken together, these studies present an exciting opportunity to discover the mechanisms that promote degradation of the toxic repeat expansion RNA and, potentially, the ability to accelerate its decay to reduce toxicity. If successful, the knowledge gained from this work could guide future therapeutic design for c9ALS/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 = -$9,105 )
2026	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Aging Research	000	3	1/27/2026	NON-COMPETING CONTINUATION	-$9,105
														Subtotal = -$9,105

Issue Date FY: 2024 ( Subtotal = $41,740 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Aging Research	000	3	5/24/2024	NON-COMPETING CONTINUATION	$41,740
														Subtotal = $41,740

Issue Date FY: 2023 ( Subtotal = $40,262 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Aging Research	000	2	2/10/2023	NON-COMPETING CONTINUATION	$40,262
														Subtotal = $40,262

Issue Date FY: 2022 ( Subtotal = $39,127 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Aging Research	001	1	2/9/2022	NEW	$0
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Aging Research	002	1	5/6/2022	NEW	$717
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Aging Research	000	1	2/9/2022	NEW	$38,411
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Aging Research	003	1	8/30/2022	NEW	-$1
														Subtotal = $39,127

Grand Total All Awards = $112,024

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Understanding and Manipulating the Degradation of the C9orf72 Repeat Expansion RNA

Award Number: F30AG076323

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/01/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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