Msh3 and Pms1 Set Neuronal CAG-repeat Migration Rate to Drive Selective Striatal and Cortical Pathogenesis in HD Mice

Published: July 13, 2024

SUMMARY Modifiers of Huntington’s disease (HD) include mismatch repair (MMR) genes; however, their underlying disease-altering mechanisms remain unresolved. Knockout (KO) alleles for 9 HD GWAS modifiers/MMR genes were crossed to the Q140 Huntingtin (mHtt) knock-in mice probe such mechanisms. Four KO strongly ( Msh3 and Pms1 ) or moderately Msh2 Mlh1 rescue a triad adult-onset, striatal medium-spiny-neuron (MSN)-selective phenotypes: somatic Htt DNA CAG-repeat expansion, transcriptionopathy, mHtt protein aggregation. Comparatively, cortex also exhibits an analogous, but later-onset, pathogenic that is -dependent. Remarkably, Q140/homozygous Msh3-KO lacks visible aggregates in brain, even at advanced ages (20-months). Moreover, -deficiency prevents synaptic marker loss, astrogliosis, locomotor impairment mice. Purified MSN nuclei exhibit highly linear age-dependent repeat expansion (i.e. migration), with modal-CAG increasing +8.8 repeats/month (R 2 =0.98). This rate reduced 2.3 0.3 heterozygous homozygous alleles, respectively. Our study defines thresholds below which there are no detectable nuclear neuropil aggregates. Mild transcriptionopathy can still occur stabilized 140-CAG repeats, majority transcriptomic changes due expansion. analysis reveals 479 expression levels correlated length MSNs. Thus, our mechanistically connects selective neuronal vulnerability HD, set migration drive repeat-length dependent pathogenesis; provides preclinical platform targeting these suppression across brain regions. One Sentence Summary genetic drivers sequential cortical pathogenesis by mediating vulnerable neurons.

Language: Английский

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Sex Differences in a Novel Mouse Model of Spinocerebellar Ataxia Type 1 (SCA1)

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(6), P. 2623 - 2623

Published: March 14, 2025

Spinocerebellar ataxia type 1 (SCA1) is a rare autosomal dominant inherited neurodegenerative disease caused by the expansion of glutamine (Q)-encoding CAG repeats in gene ATAXIN1 (ATXN1). Patients with SCA1 suffer from movement and cognitive deficits severe cerebellar pathology. Previous studies identified sex differences progression patients, but whether these are present mouse models unclear. Using battery behavioral tests, immunohistochemistry brain slices, RNA sequencing, we examined motor performance, pathology, expression changes recently created conditional knock-in model f-ATXN1146Q expressing human coding regions ATXN1 146 repeats. We found worse performance weight loss accompanied increased microglial activation an increase immune viral response pathways male mice.

Language: Английский

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Uncontrolled CAG expansion in neurons susceptible to Huntington's disease

The Lancet Neurology, Journal Year: 2025, Volume and Issue: 24(4), P. 282 - 284

Published: March 20, 2025

Language: Английский

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An expanded polyglutamine in ATAXIN1 results in a loss-of-function that exacerbates severity of Multiple Sclerosis in an EAE mouse model

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: April 14, 2025

Background and Objectives Ataxin-1 (ATXN1) is a protein in which expansion of its polyglutamine tract causes the neurodegenerative disorder spinocerebellar ataxia type 1 (SCA1) via gain-of-function. Wild ATXN1 was recently shown to have protective role regulating severity experimental autoimmune encephalomyelitis (EAE), well-established mouse model for Multiple sclerosis (MS). This study further investigates with an expanded context MS using EAE model. Methods Hemizygous Atxn1 (Atxn1^2Q/−) mice or f-ATXN1^146Q/2Q, heterozygous that one copy endogenous gene replaced polyQ pathogenic human ATXN1 gene, were injected myelin oligodendrocytes glycoprotein (MOG_{35 − 55}) peptide induce EAE. Immunohistochemical biochemical approaches used analyze degree demyelination, cell loss, axonal degeneration as well detecting activated immune cells inflammatory cytokines upon induction Atxn1^2Q/− f-ATXN1^146Q/2Q mice. Results Our findings reveal loss-of-function wild Atxn1 f-ATXN1^146Q/2Q significantly exacerbates symptoms, leading increased heightened axon degeneration, greater clinical disability affected Importantly, data reveals neurotoxic astrocytes are at acute stage disease (PID-14) chronic (PID-30) no longer show signs activation. The also demonstrated enhanced infiltration into lesions mutant Discussion These results indicate plays modulating responses maintaining neural integrity during MS. ATXN1’s ability dampen response. Understanding functional pathogenesis may open new avenues therapeutic strategies aimed mitigating progression.

Language: Английский

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A Neural Basis for Mutant ATAXIN-1 Induced Respiratory Dysfunction in Mouse Models of Spinocerebellar Ataxia Type 1

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 20, 2024

Abstract Spinocerebellar ataxia type 1 (SCA1), a dominantly inherited neurodegenerative disorder caused by an expanded trinucleotide repeat in the ATAXIN-1 (ATXN1) gene, is characterized motor dysfunction, cognitive impairment, and death from compromised swallowing respiration. To delineate specific cell types that contribute to respiratory we utilized floxed conditional knock-in f-ATXN1 146Q/2Q mouse. Whole body plethysmography during spontaneous respiration challenge showed mice exhibit phenotype elevated frequency, volumes, output. Consequently, ability of increase ventilation impaired. investigate role mutant ATXN1 expression neural skeletal muscle lineages, were bred Nestin-Cre Acta1-Cre respectively. These analyses revealed abnormal involved two aspects: behavioral which SCA1 increased activity testing functional dysregulation central control centers. Both aspects partially ameliorated removing neural, but not muscle, lineages.

Language: Английский

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