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Molecular mechanisms of triplet repeat instability in Huntington's disease

Award Number: R56NS118082
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: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Molecular mechanisms of triplet repeat instability in Huntington's disease - Project Summary/Abstract Huntington’s disease (HD) is a neurodegenerative disorder caused by an expansion of a CAG repeat tract within the huntingtin (HTT) gene, leading to neuronal death primarily in the striatum and the cortex. The CAG repeat is highly unstable and patients with longer inherited CAG repeats develop the disease at an earlier age. The repeat tract is also highly unstable in somatic cells. A high degree of age-dependent somatic expansion of the CAG repeat is observed in neurons of both the striatum and the cortex of HD patients. Earlier disease onset is also associated with the length of uninterrupted CAG repeats and a concomitant increase in somatic instability. These findings further underscore the importance of somatic CAG expansion in disease manifestation. Genome-wide association studies in affected individuals have revealed the existence of genetic modifiers of the age of onset of the disease; these include several genes of the mismatch repair pathway (MMR) (MSH3, MLH1, PMS1, MLH3 and PMS2) as well as FAN1, a DNA interstrand cross-link repair gene. Independently, studies in mouse models of HD have revealed that genetic knockout of the MMR genes, Msh2, Msh3, Mlh1, Mlh3, or Pms1 reduces somatic instability of CAG repeats in the striatum, and inactivation of Fan1 increases CAG repeat expansion. Our studies have revealed a competition between MMR and FAN1 for extrahelical extrusions (structures formed within repetitive sequences), that is controlled by protein levels and DNA conformational dynamics. We have discovered that FAN1 nuclease cleaves extrahelical extrusions in a reaction that requires DNA-loaded PCNA, and this process leads to extrusion removal. In this proposal, we plan to expand on our initial findings, with the overarching goal to integrate biochemical, structural, and cellular approaches to develop a unified understanding of the mechanism of tissue/cell type specific CAG repeat expansion, and to enable development of novel therapeutic strategies for treatment of triplet repeat diseases. In Aim 1, we will investigate the FAN1-PCNA interaction and its modulatory effects on CAG repeat expansion. In Aim 2, we will determine how PMS1 drives CAG repeat expansion. In Aim 3, we will identify striatal neuronal factors involved in CAG repeat expansion and profile their role(s) in this process. Completion of these studies will not only shed light on the mechanisms of CAG repeat expansion in HD but also will inform our understanding the role of DNA repair proteins in the somatic instability process in other triplet repeat diseases including fragile-X related disorders (FXDs), and myotonic dystrophy type 1.


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 = $539,089 )
2026	2026	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	9/17/2026	COMPETING CONTINUATION	$539,089
														Subtotal = $539,089

Grand Total All Awards = $539,089

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Molecular mechanisms of triplet repeat instability in Huntington's disease

Award Number: R56NS118082

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: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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