Huntingtin lowering reduces somatic instability at CAG-expanded loci

Abstract

Expanded trinucleotide repeats cause many human diseases, including Huntington’s disease (HD). Recent studies indicate that somatic instability of these repeats contributes to pathogenesis in several expansion disorders. We find that lowering huntingtin protein (HTT) levels reduces somatic instability of both the Htt and Atxn2 CAG tracts in knockin mouse models, and the HTT CAG tract in human iPSC-derived neurons, revealing an unexpected role for HTT in regulating somatic instability.

Di-valent siRNA Mediated Silencing of MSH3 Blocks Somatic Repeat Expansion in Mouse Models of Huntington’s Disease

“…We found that di-siRNA-mediated modulation of HTT had no effect on somatic repeat expansion in vivo . This finding contradicts an early preprint study in which antisense oligonucleotide (ASO)-mediated silencing of Htt reduced somatic repeat expansion ( 41 ). It is likely that the Htt -targeting ASOs reduce somatic repeat expansion by interfering with locus transcriptional rates through binding nascent nuclear targets.…”

“…Near complete silencing of Htt with di-valent siHTT_10150 had no measurable impact on somatic repeat expansion (instability index = 8.4±0.5) (Fig. 2H), contrasting previous HTT-lowering ASO results in this mouse model ( 41 ).…”

“…2A)( 30 ) with a 5’-Vinylphosphonate to chemically stabilize the 5’ phosphate ( 33, 40 ). Because silencing of Htt mRNA with an antisense oligonucleotide (ASO) was previously shown to block somatic repeat expansion in Hdh Q111 mice ( 41 ), we also used a previously-validated di-valent siRNA targeting Htt (siHTT_10150) as a control ( 30, 42 ). Lead or control compounds (10 nmol, or 125 μg dose) were delivered to 12-week-old Hdh Q111 mice (n = 6 per group) via intracerebroventricular (ICV) injection (Fig.…”

DNA Mismatch Repair and its Role in Huntington’s Disease

“…One implication of these observations is that factors that hasten or attenuate CAG-repeat instability may also be expected to affect disease onset. It is noteworthy that a recent study has suggested a role for huntingtin protein levels in promoting CAG repeat expansion in knock-in mouse models of HD and spinocerebellar ataxia type 2, as well as in HD patient iPS-derived medium spiny neurons, although the pathways underlying these effects are yet to be delineated [157].…”

Kinetin/N6-furfuryladenine: A New Neurodegenerative Disease Lead from an Old Plant Cytokine

“…This suggests huntingtin activity in DNA repair and dysfunction of mutant huntingtin may be contributing to the somatic expansion of its own gene. Indeed, one intriguing study indicates the CAG expansion in another CAG repeat disease gene, spinocerebellar ataxia type 2 (SCA2), can be affected by huntingtin levels [29].…”