Gidney, F. | Search bioRxiv

bioRxiv2026

Genetic or pharmacological disruption of the MSH3 Y245/K246 IDL binding pocket slows CAG repeat expansion

Recent genetic studies have shown somatic expansion of the CAG repeat is the key process driving Huntingtons disease (HD) pathogenesis. Recognition of insertion deletion loops (IDLs), lesions prone to form within the CAG repeat, by Muts{beta} (MSH3/MSH2) is thought to be the primary event in the expansion process. This starts a cascade that leads to error prone repair and incorporation of additional CAG units into the repeat. In vitro data shows MSH3 binds IDLs through a DNA binding pocket formed by MSH3 residues Y245/K246. In this study, we investigated the significance of this DNA binding motif in CAG repeat expansion using cell lines harboring long, unstable HTT CAG repeats. Genetic disruption of the MSH3 Y245/K246 motif significantly reduced DNA interaction, exhibited MMR deficiency in a frameshift mutator assay and abrogated repeat expansion in a U2OS cell line expressing mutant HTT exon 1. Pharmacological blockade of this site using a small molecule targeting the DNA binding pocket similarly reduced DNA binding and repeat expansion in a U2OS cell line. Crucially, this molecule also slowed CAG repeat expansion in medium spiny neurons derived from HD patient-iPSCs. Targeting of the MSH3 IDL binding pocket may represent a possible therapeutic strategy.

neuroscience↗

bioRxiv2018

Adipokines contribute to central-obesity related reductions in myelin-sensitive MRI indices in the fornix.

Midlife obesity is a risk factor of late onset Alzheimers disease (LOAD) but why this is the case remains unknown. As systemic inflammation is involved in both conditions, one possibility is that obesity-related neuroinflammation may contribute to the development of LOAD. Neuroinflammation is closely linked to white matter myelin loss, and this can be measured in vivo with quantitative magnetization transfer (qMT) imaging. Here, we investigated whether differences in obesity measures, i.e., in Waist Hip Ratio (WHR), abdominal visceral and subcutaneous fat volume fractions and Body Mass Index (BMI), were associated with reductions in qMT indices of apparent myelin in temporal white matter pathways involved in LOAD (i.e., the fornix, the parahippocampal cingulum and the uncinate fasciculus compared with whole brain and cortico-spinal white matter) in 166 cognitively healthy individuals (38-71 years of age). Obesity-related effects on myelin-sensitive markers were contrasted with differences in apparent axon density from dual-shell diffusion Neurite Orientation Dispersion and Density Imaging (NODDI). Differences in WHR and in visceral fat volume fractions were negatively correlated with differences in qMT estimates of apparent myelin and tissue metabolism in the fornix but not with any other microstructural components. These correlations were not explained by demographic (age, sex, education), health (hypertension, alcohol consumption, sedentary lifestyle) or genetic (APOE genotype, family history of dementia) risk factors of LOAD. Furthermore, differences in the ratio of plasma concentrations of leptin and adiponectin were also positively correlated with differences in C-Reactive Protein concentrations, and contributed significantly to the correlations between central obesity and myelin-sensitive metrics in the fornix. These results are consistent with the view that visceral fat-related chronic inflammation may damage white matter myelin in limbic regions, known to be vulnerable to LOAD pathology.

neuroscience↗