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Defining mechanisms underlying C9orf72-associated frontotemporal dementia with C. elegans and mammalian models

Award Number: R01NS124802
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Defining mechanisms underlying C9orf72-associated frontotemporal dementia with C. elegans and mammalian models - Frontotemporal dementia (FTD) is the second most common type of inherited dementia following Alzheimer’s disease. FTD is caused by the progressive neurodegeneration of cells in the frontal and temporal lobe of the cerebral cortex. Expansion of a GGGGCC (G4C2) sequence in the first intron of the C9orf72 gene is the most common genetic cause of FTD and is responsible for ~25% of cases. The mechanisms by which expansion of the G4C2 sequence lead to neurodegeneration of specific neurons is incompletely understood. G4C2 RNA is transcribed in both sense and antisense directions and both RNA strands can undergo an unusual type of translation called Repeat Associated non-AG dependent translation (RANT). RANT of the sense and antisense G4C2 RNA produces five distinct dipeptide repeat proteins (DPRs), two of which (PR and GR) confer strong toxicity in multiple model systems. To better understand the pathogenesis of C9orf72-mediated FTD, we generated C. elegans models expressing pure DPRs. Both PR and GR were toxic in worms and caused neurodegeneration. To define genes and pathways causing toxicity, we performed an unbiased genetic suppressor screen and discovered several highly conserved genes that blocked PR50 toxicity. One highly conserved suppressor is the nuclear E3 ligase adaptor SPOP. SPOP is widely studied in cancer since SPOP missense mutations are a major genetic cause of prostate and endometrial cancer. However, SPOP has never been linked to a neurodegenerative disease until now. The role of SPOP in DPR toxicity is conserved, since both SPOP genetic knockdown and an SPOP small molecule inhibitor blocks DPR toxicity in mammalian primary neurons. One major SPOP target in cancer is BRD2/3/4, which are bromodomain-containing transcriptional regulatory proteins. We found that inhibition of the BRD homolog bet-1 suppresses the ability of SPOP mutants to protect against DPR toxicity. Based on these findings, we hypothesize that the SPOP pathway, which is currently being targeted for the treatment of cancer, may also underlie neurodegenerative pathology in C9 disease. To test this hypothesis, we will: 1) determine whether DPRs directly interact with SPOP to modulate known pathological pathways, such as defective nuclear transport and stress granule formation; 2) delineate the mechanism by which SPOP, BRD, and possibly other substrates mediate DPR toxicity; and 3) determine if SPOP is a ‘druggable’ target for neuroprotection against DPRs in mammalian neurons. Our studies will interrogate a novel pathway associated with C9 disease using a diversity of approaches and experimental model systems. The discovery of this novel ubiquitination system could lead to new therapeutic insights for this incurable form of dementia.


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: 2025 ( Subtotal = $654,898 )
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/24/2025	NON-COMPETING CONTINUATION	$654,898
														Subtotal = $654,898

Issue Date FY: 2024 ( Subtotal = $736,797 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/26/2024	NON-COMPETING CONTINUATION	$73,680
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/18/2024	NON-COMPETING CONTINUATION	$663,117
														Subtotal = $736,797

Issue Date FY: 2023 ( Subtotal = $745,651 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/6/2023	NON-COMPETING CONTINUATION	$745,651
														Subtotal = $745,651

Issue Date FY: 2022 ( Subtotal = $766,890 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/18/2022	NEW	$766,890
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	1/25/2022	NEW	$0
														Subtotal = $766,890

Grand Total All Awards = $2,904,236

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Defining mechanisms underlying C9orf72-associated frontotemporal dementia with C. elegans and mammalian models

Award Number: R01NS124802

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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