Biology subjects

Horvath, S.

Publications and source records attributed to Horvath, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Systemic control and inter-organ communication of ovarian aging

Whether ovarian aging is intrinsic and unidirectional or dynamically regulated by systemic context remains an open question for fertility and women's healthspan. To address it, we developed a mouse ovarian transcriptomic aging clock (OvaAge) and applied it, together with published transcriptomic, epigenetic and pathway-resolved DNA methylation (PathAge) clocks, multi-omic analyses and reproductive outcomes, to new reciprocal heterochronic ovary transplantation and parabiosis experiments. Ovarian molecular age shifted in both directions: aged ovaries became younger in young hosts and young ovaries became older in aged hosts, and in each case the shift was partial across transcriptomic, epigenetic and pathway-resolved measures. Ovaries from 13-month-old C57BL/6J donors supported full-term pregnancies and live births at 17-18 months of age when transplanted into young hosts, but not when transplanted into old hosts, and young ovaries supported live births in 17-18-month-old recipients. Donor ovary age altered the transcriptomic age of the uterus in both directions, while young ovaries also lowered the transcriptomic age of aged liver and brain, identifying the ovary as an active node within an inter-organ aging network. Across unilateral and bilateral transplantation and parabiosis, an older environment increased inflammatory gene expression in the ovary, whereas a younger environment reduced it and increased mitochondrial and biosynthetic programs. Integration of methylation, expression and cell-type markers linked these changes to declining oocyte-associated programs and an expanding stromal compartment enriched for multinucleated giant cells (MNGCs). MNGC-rich regions formed a reversibly remodeled, focally aged niche with distinct spatial metabolic features, and a related macrophage expression signature was detected in human ovaries. Together, these findings identify ovarian aging as a modular, bidirectionally plastic process that is regulated by the systemic environment and point to tractable intervention points.

systems biology↗

bioRxiv2026

Transplanted hearts assimilate the recipient's biological age

Background. Despite the growing demand for transplantation, a shortage of donor organs persists, limiting access to this lifesaving procedure. To meet the increasing demand, organs are frequently transplanted across an age discrepancy between donor and recipients. Methods. We delineated biological age dynamics in heterochronic heart transplants performed in both mice and patients. We carried out multiomic profiling and applied advanced biomarkers of aging to understand the interactions between the transplanted organ and the host. Results. We show that the biological age of experimental heart transplants rapidly assimilates the age of recipients. Interestingly, this effect was limited to the grafted tissue without reciprocal effects on systemic biological age of the recipient. These effects were confirmed at the level of DNA methylation and gene expression. Extending our findings clinically using both omics and functional analyses, we show that the biological age of heterochronically transplanted hearts is strongly associated with the age of the recipient, rather than the donor, confirming the clinical relevance of our experimental findings. Conclusions. These data identify the systemic environment as a driving force on tissue biological age. The rejuvenation of older organs in young recipients suggests novel approaches to organ allocation that may expand the pool of transplantable organs.

systems biology↗

bioRxiv2026

Effects of long-term fasting: longitudinal epigenetic responses in humans

Prolonged fasting induces marked metabolic adaptations, but whether such time-limited yet intensive interventions engage molecular processes related to biological aging in humans remains unclear. To address this, we investigated physiological and epigenetic responses to a 12-day medically supervised fasting intervention with longitudinal follow-up in 32 participants. Fasting elicited coordinated systemic physiological changes across metabolic and hematological parameters, with partial persistence at one month. Genome-wide DNA methylation analyses revealed modest but detectable CpG-level changes, primarily emerging at follow-up and distributed across genomic contexts. In parallel, epigenetic aging clocks showed clock-specific and time-dependent responses, with substantial inter-individual variability. Lower baseline epigenetic age acceleration was consistently associated with greater fasting-induced weight loss, suggesting a link between epigenetic state and metabolic responsiveness. Together, these findings indicate that prolonged fasting induces coordinated physiological adaptations alongside structured changes in epigenetic aging measures that are not captured by conventional clinical biomarkers. This study highlights epigenetic clocks as integrative molecular readouts for probing aging-related responses to short-term metabolic interventions, while also delineating their current interpretive limits.

genomics↗

bioRxiv2026

Large-scale Perturbation of Systems Biology-Derived Genes Reveals Modifiers of HD-associated Transcriptomic Networks and Pathology

In Huntingtons disease (HD), disease-driver genes are broadly expressed, but pathogenic players specific to vulnerable neurons remain poorly defined. Leveraging a previously defined mutant huntingtin (mHtt) CAG-length-associated gene network, we perturbed 115 module hub genes with heterozygous knockout (KO-het) to assess their striatal transcriptomic modifier effects in wildtype and Q140 HD mice. We generated 3,592 striatal RNA-seq datasets, mapped 6,517 perturbagen-responder gene pairs, and uncovered regulators of medium spiny neuron (MSN) identity gene expression and DNA- methylase/demethylase-sensitive genes. We developed a bioinformatic pipeline to rank the perturbations with significant impacts on striatal transcriptome and HD-associated gene networks in wildtype or Q140 mice. KO-het for FoxP1 and Scn4b (two MSN-selective genes) exacerbated, whereas Pdp1 KO-het ameliorated, Q140 striatal pathology. Importantly, knockdown of functionally opposing ion channels, SCN4B and KCNH4, dichotomously affected aggregation and neurodegeneration in reprogrammed HD patient MSNs. Together, our study rigorously evaluated systems biology-derived candidates to identify modifiers of HD-associated molecular networks and pathology, providing an in vivo perturbation- transcriptome resource and highlighting genes involved in MSN excitability, transcription, calcium signaling, and mitochondrial metabolism in HD pathogenesis.

genetics↗

bioRxiv2025

Beyond the Genotype: A Multi-Omic Analysis of APOEe4's Role in Alzheimer's Disease

Alzheimers disease (AD) is characterized by widespread molecular dysregulation, with the APOEe4 allele recognized as its strongest genetic risk factor. However, the mechanisms by which APOEe4 drives distinct molecular changes - whether by exacerbating pathology or triggering compensatory responses - remain incompletely understood. We generated and analyzed proteomic, epigenetic, and genetic data from post-mortem dorsolateral prefrontal cortex samples of a uniquely APOEe4-enriched subset of the Religious Orders Study and Memory and Aging Project (ROSMAP). Specifically, we generated DIA LC-MS proteomic data (n = 302), analyzed previously generated DNA methylation profiles from our group (n = 310), and used published whole-genome sequencing data (n = 254) to compute polygenic risk scores (PRS). In this cohort, 69% (n = 214) were APOEe4 carriers, and 19.6% (n = 42) of them showed no pathological evidence of AD based on NIA-Reagan criteria, enabling identification of APOEe4-related risk and resilience mechanisms. In the absence of AD, APOEe4 carriers exhibited lower levels of 27 proteins, suggesting early synaptic (e.g., VAMP1, SYN3, CASKIN1) and metabolic (e.g., GLUD1, PI4KA) vulnerability. By contrast, APOEe4 carriers with AD displayed marked upregulation of inflammatory and proteostatic proteins (e.g., GNAO1, AHNAK, FGG, HEBP1, APEX1, RAB4A, SLC12A5, LRP1, BAG6) and hypermethylation of cg06329447 in ELAVL4. Network analyses highlighted convergent disruptions in synaptic transmission, metabolism, and proteostasis - key pathways altered in APOEe4-associated AD. Mediation analyses identified GRIPAP1 and GSTK1 as top protein mediators (accounting for [~]26-33% of APOEe4s effect), with VAMP1, CASKIN1, DPP3, SYN3, and FGG each contributing [~]9-15%. ELAVL4 hypermethylation also mediated [~]12% of the APOEe4 effect, linking epigenetic dysregulation to disease risk. To assess whether the identified proteins reflected broader genetic risk for AD or were specific to APOEe4, we calculated PRS both excluding and including the APOE genomic region. While the non-APOE PRS showed no association with identified molecular markers, the APOE-inclusive PRS was significantly associated with eight AD-related proteins in carriers, indicating they are not explained by polygenic risk outside of APOE. Finally, predictive modeling stratified by APOEe4 status revealed that in non-carriers, PRS most effectively classified AD (AUC = 0.73), whereas in carriers, proteomic and epigenetic markers outperformed PRS (AUC up to 0.74). Together, these findings demonstrate that APOEe4 confers AD risk through early synaptic and metabolic disruptions and later-stage inflammatory and epigenetic changes, laying the groundwork for genotype-tailored biomarker development and therapeutic strategies. VISUAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=156 HEIGHT=200 SRC="FIGDIR/small/682426v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1477a2forg.highwire.dtl.DTLVardef@1a6d173org.highwire.dtl.DTLVardef@1010821org.highwire.dtl.DTLVardef@bcde3a_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2025

Sex-specific non-linear DNA methylation trajectories across aging predict cancer risk and systemic inflammation

Aging is a multi-modal process, leaving distinct signatures across molecular layers, including the epigenome. DNA methylation changes are among the most robust markers of biological aging. Yet, most studies rely on models assuming linear relationships with age and often analyze mixed-sex cohorts, overlooking well-known sex differences in the timing and nature of aging phases. Such approaches risk obscuring critical, non-linear transitions and sex-specific trajectories that may better capture the biology of aging. We developed a computational approach to detect complex, non-linear trajectories and disentangle shared from sex-divergent patterns. Applied to whole-blood deconvoluted methylomes from 252 females and 246 males spanning ages 19-90 years, this analysis revealed convergent and divergent epigenetic aging pathways independent of immune cell composition. These non-linear trajectories were enriched for developmental transcription factor binding motifs, including NF1/CTF and REST, which are known for their oncogenic potential. Strikingly, a female-specific non-linear cluster was robustly associated with cancer onset and systemic inflammation. Our results uncover sex-specific, non-linear aging programs that better capture the dynamics of epigenetic change than linear models. These findings nominate candidate biomarkers for early disease risk and offer mechanistic insight into how aging trajectories diverge between the sexes.

molecular biology↗

bioRxiv2025

DNA Methylation Ageing Atlas Across 17 Human Tissues

Aging involves widespread epigenetic remodeling across tissues, yet the nature and consistency of these changes remain unclear. We conducted a meta-analysis of more than 15,000 human methylomes spanning 17 tissues, identifying both conserved and tissue-specific aging signatures. We examined linear changes via differentially methylated positions, variability shifts via variably methylated positions, and Shannon-entropy to capture methylation disorder. Network analysis revealed fragile co-methylation modules largely resistant to beneficial perturbation. Key disruptors, including PCDHGA1, MEST, HDAC4, and HOX genes, exacerbated aging signals across tissues. Notably, a resilient module enriched for NAD{square} salvage metabolism supports therapeutic targeting of NAD{square} in aging. PCDHGA1 emerged as a conserved cross-tissue driver, suggesting protocadherin-mediated adhesion plays a broader role in maintaining structural and signaling stability in multiple organ systems. Our open-access atlas provides a foundational resource for dissecting the molecular architecture of human aging and identifying testable targets for intervention, biomarkers, and translational epigenetic therapies.

bioinformatics↗

bioRxiv2025

Dental aging offers new insights to the first epigenetic clock for common dolphins (Delphinus delphis)

Determining exact age in wild odontocetes is essential for understanding population dynamics, survival, and reproduction, yet remains logistically challenging. While epigenetic aging is emerging as a valuable approach, only nine species-specific clocks currently exist. Most have been calibrated using captive known-age animals or well-studied wild populations. Only two previous studies have used dental ages from stranded or bycaught individuals. This is due to concerns that dental age inaccuracies, especially in older animals, may affect epigenetic clock performance. To explore this, we developed the first species-specific epigenetic clock for common dolphins (Delphinus delphis), analysing DNA methylation at 37,492 cytosine-phosphate-guanine sites in skin samples from stranded and bycaught dolphins with estimated dental ages. Elastic net models with Leave-One-Out Cross-Validation were applied to three subsets: the relaxed subset (all individuals; n = 75, median absolute error (MAE) = 2.02, r = 0.81, R2 = 0.66), the strict subset (excluding individuals with minimum dental age estimates only; n = 73, MAE = 2.29, r = 0.81, R2 = 0.66), and the restricted subset (excluding outliers with prediction errors > 6 years; n = 63, MAE = 1.80, r = 0.91, R2 = 0.82) to compare performance. Our models consistently underestimated the age of dolphins >16 years, even when minimum dental ages were applied, suggesting absolute errors between dental and epigenetic estimates unlikely reflect dental aging error. Additionally, post-mortem decomposition condition code (DCC 1 to 3) did not affect age prediction, signalling promise for future epigenetic clocks calibrated with strandings and bycaught individuals.

genetics↗

bioRxiv2025

Molecular signatures of longevity identify compounds that extendmouse lifespan and healthspan

Longevity interventions in mammals are typically discovered on a case-by-case basis, hindering systematic geroprotector development. We developed a platform for the identification of longevity interventions integrating longevity gene expression biomarkers within and across species, in silico chemical screening, analyses of selected compounds in cell culture, short-term dietary interventions coupled with omics profiling, and ultimately lifespan studies in mice. This approach identified compounds (selumetinib, vorinostat, celastrol, AZD-8055, LY-294002) that extended lifespan and/or healthspan in aged C57BL/6JN male mice, with limited effects in females. In addition, selumetinib and vorinostat increased lifespan when administered to young, genetically heterogeneous UM-HET3 mice. Our biomarker-driven platform accelerates geroprotector discovery, offering a scalable approach to target conserved longevity pathways.

systems biology↗

bioRxiv2025

A DNA methylation-based clock for age estimates in the wood mouse (Apodemus sylvaticus)

Environmental stressors are expected to accelerate senescence but demonstrating this requires both a measure of senescence and knowledge of chronological age - data rarely available for most wild animals. Here, we constructed a DNA methylation-based epigenetic clock for the wood mouse (Apodemus sylvaticus) using known-aged laboratory individuals and applied it to a wild population of unknown ages. This represents one of the first demonstrations that a laboratory-trained epigenetic clock can be used to infer age structure in free-living animals. Multiple lines of evidence validated use of the clock in wild individuals: age estimates fell within expected ranges, recapitulated population demographic structure, and recovered predicted signatures of senescence, including an increase in infection probability with age. Moreover, wild mice given experimental food supplementation and parasite-removal drugs exhibited slower epigenetic ageing rates. Together, our findings demonstrate that epigenetic clocks can infer both chronological age and ageing rates in the wild, providing a powerful framework to identify the ecological and individual determinants of ageing.

genomics↗

bioRxiv2025

Epigenomic insights into extreme longevity in the world's oldest terrestrial animal, Jonathan

Giant tortoises exhibit exceptional longevity, often exceeding the human lifespan. To understand the genomic and epigenomic basis of their longevity, awe analyzed the DNA sequence and methylome of Jonathan, an Aldabra giant tortoise (Aldabrachelys gigantea), estimated to be 192 years old. Relative to other giant tortoises (Aldabrachelys gigantea and Chelonoidis abingdonii), we found Jonathan has gene variants in pathways associated with aging, including DNA repair and telomere regulation. Consistent with his advanced age, Jonathan has significant age-related changes in DNA methylation and methylation entropy, compared with a 5-year-old Aldabra individual. Notably, we found that low entropy regions in Jonathans methylome were enriched for genes involved in the electron transport chain. This suggests that high-fidelity transcription of these genes may be crucial for extreme longevity. With this data, we propose a model for aging, that links efficient mitochondrial energy production with nuclear maintenance of low methylation entropy.

genomics↗

bioRxiv2024

Defining a highly conserved B cell epitope in the receptor binding motif of SARS-CoV-2 spike glycoprotein

SARS-CoV-2 mRNA vaccines induce robust and persistent germinal centre (GC) B cell responses in humans. It remains unclear how the continuous evolution of the virus impacts the breadth of the induced GC B cell response. Using ultrasound-guided fine needle aspiration, we examined draining lymph nodes of nine healthy adults following bivalent booster immunization. We show that 77.8% of the B cell clones in the GC expressed as representative monoclonal antibodies recognized the spike protein, with a third (37.8%) of these targeting the receptor binding domain (RBD). Strikingly, only one RBD-targeting mAb, mAb-52, neutralized all tested SARS- CoV-2 strains, including the recent KP.2 variant. mAb-52 utilizes the IGHV3-66 public clonotype, protects hamsters challenged against the EG.5.1 variant and targets the class I/II RBD epitope, closely mimicking the binding footprint of ACE2. Finally, we show that the remarkable breadth of mAb-52 is due to the somatic hypermutations accumulated within vaccine-induced GC reaction. One Sentence SummaryBooster SARS-CoV-2 mRNA vaccine recruits and broadens GC B cell responses targeting a highly conserved site on receptor binding domain of spike glycoprotein.

immunology↗

bioRxiv2024

Systematic dissection of epigenetic age acceleration in normal breast tissue reveals its link to estrogen signaling and cancer risk

Breast aging encompasses intricate molecular and cellular changes that elevate cancer risk. Our study profiled DNA methylation and gene expression of 181 normal breast samples and systematically evaluated eight epigenetic clocks. We found that clocks trained using breast tissues demonstrate improved age prediction in normal breast tissue, and bias universally exists in epigenetic clocks, necessitating a proper definition of age acceleration. Cell composition analysis revealed significant age-related alterations and highlighted its distinct associations with age acceleration, including increased luminal epithelial and myoepithelial cells and reduced adipocytes and immune cells, connecting age acceleration to carcinogenesis from a cell compositional perspective. Additionally, CpG sites associated with age acceleration were enriched for estrogen receptor binding sites, providing a mechanistic link between estrogen exposure, accelerated aging, and cancer. These findings highlight the importance of cellular heterogeneity in epigenetic age estimates and the potential of age acceleration to guide for risk stratification and prevention strategies.

bioinformatics↗

bioRxiv2024

CpGPT: a Foundation Model for DNA Methylation

DNA methylation is a type of epigenetic modification that plays a significant role in development, aging, and disease. Despite extensive research, how genome-wide DNA methylation patterns collectively encode and influence complex phenotypes such as aging and disease remains difficult to characterize with conventional approaches. Foundation models are a class of machine learning model that leverage vast quantities of data to make sense of complex data types, such as genome sequences or single-cell transcriptomes. Here, we present the Cytosine-phosphate-Guanine Pretrained Transformer (CpGPT), a novel foundation model pretrained on CpGCorpus, a novel database with more than 2,000 DNA methylation datasets encompassing over 150,000 samples from diverse conditions. CpGPT lever-ages an improved transformer architecture to learn comprehensive representations of methylation patterns, allowing it to impute and reconstruct genome-wide methylation profiles from limited input data. By capturing sequence, positional, and epigenetic contexts, CpGPT outperforms specialized models when finetuned for aging-related tasks, including the state-of-the-art GrimAge2 and PCGrimAge for mortality and morbidity estimation. The model is highly adaptable and can impute beta values across different methylation platforms, tissue types, mammalian species, and even single-cell data. As a foundation model, CpGPT can be leveraged as a new tool for biological discovery in the field of epigenetics. The open-source code and model can be found at http://github.com/lucascamillomd/CpGPT. HighlightsO_LICpGPT is a novel foundation model for DNA methylation analysis, pretrained on over 2,000 datasets encompassing 150,000+ samples. C_LIO_LIThe model demonstrates strong performance in zero-shot tasks including imputation, array conversion, and reference mapping. C_LIO_LICpGPT achieves state-of-the-art results in mortality prediction and chronological age estimation. C_LI

systems biology↗

bioRxiv2024

Compatibility and comparative analysis of chronological and biological aging between the legacy 450K and the EPIC v2.0 arrays

Several different epigenetic clocks built from DNA methylation beadchip arrays, including the Illumina Infinium Human Methylation 450K and EPICv1 BeadChips, have been developed and are used to evaluate biological aging. However, there is still limited information on effectively utilizing the novel EPICv2 arrays and addressing biases in epigenetic clock calculations resulting from missing probes initially present on legacy arrays. We address how the absence of probes on the EPICv2 array, originally present on the 450K array, affects many available epigenetic clock estimates. Using data from the InCHIANTI study of aging, our findings show that while clocks like Hannum and GrimAgeV2 exhibit significant over- or underestimation due to missing probes, the correlations between estimates from all 450K probes (unreduced) and those from shared probes between 450K and EPICv2 (reduced) remain strong. In this cohort, we consider AgeAcceleration from traditional epigenetic clocks to be the most reliable approach. Their values do not significantly change upon probe reduction, with unreduced and reduced values being nearly identical and with stable mean differences across chronological age.

genetics↗

bioRxiv2024

Axolotl epigenetic clocks offer insights into the nature of negligible senescence

Renowned for their regenerative abilities, axolotls also exhibit exceptional longevity, resistance to age-related diseases and apparent lack of physiological declines through lifespan, and have thus been considered organisms of negligible senescence. Whether axolotls display epigenetic hallmarks of ageing remains unknown. Here, we probe the axolotl DNA methylome throughout lifespan and present its first epigenetic clocks. Both at tissue-specific or pan-tissue levels, the clocks are biphasic, capable of predicting age during early life but not for the rest of its lifespan. We show that axolotls exhibit evolutionarily conserved features of epigenetic ageing during early life, yet their methylome is remarkably stable across lifespan, including at Polycomb Repressive Complex 2 (PRC2) target sites, suggesting that this species deviates from known patterns of epigenetic ageing. This study provides molecular insights into negligible senescence and furthers our understanding of ageing dynamics in animals capable of extreme regeneration.

developmental biology↗

bioRxiv2024

Loss of H3K9 trimethylation leads to premature aging

Aging is the major risk factor for most human diseases and represents a major socio-economical challenge for modern societies. Despite its importance, the process of aging remains poorly understood. Epigenetic dysregulation has been proposed as a key driver of the aging process. Modifications in transcriptional networks and chromatin structure might be central to age-related functional decline. A prevalent feature described during aging is the overall reduction in heterochromatin, specifically marked by the loss of repressive histone modification, Histone 3 lysine 9 trimethylation (H3K9me3). However, the role of H3K9me3 in aging, especially in mammals, remains unclear. Here we show using a novel mouse strain, (TKOc), carrying a triple knockout of three methyltransferases responsible for H3K9me3 deposition, that the inducible loss of H3K9me3 in adulthood results in premature aging. TKOc mice exhibit reduced lifespan, lower body weight, increased frailty index, multi-organ degeneration, transcriptional changes with significant upregulation of transposable elements, and accelerated epigenetic age. Our data strongly supports the concept that the loss of epigenetic information directly drives the aging process. These findings reveal the importance of epigenetic regulation in aging and suggest that interventions targeting epigenetic modifications could potentially slow down or reverse age-related decline. Understanding the molecular mechanisms underlying the process of aging will be crucial for developing novel therapeutic strategies that can delay the onset of age-associated diseases and preserve human health at old age specially in rapidly aging societies.

physiology↗

bioRxiv2024

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

Modifiers of Huntingtons 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 to probe such mechanisms. Four KO mice strongly (Msh3 and Pms1) or moderately (Msh2 and Mlh1) rescue a triad of adult-onset, striatal medium-spiny-neuron (MSN)-selective phenotypes: somatic Htt DNA CAG-repeat expansion, transcriptionopathy, and mHtt protein aggregation. Comparatively, Q140 cortex also exhibits an analogous, but later-onset, pathogenic triad that is Msh3-dependent. Remarkably, Q140/homozygous Msh3-KO lacks visible mHtt aggregates in the brain, even at advanced ages (20-months). Moreover, Msh3-deficiency prevents striatal synaptic marker loss, astrogliosis, and locomotor impairment in HD mice. Purified Q140 MSN nuclei exhibit highly linear age-dependent mHtt DNA repeat expansion (i.e. repeat migration), with modal-CAG increasing at +8.8 repeats/month (R2=0.98). This linear rate is reduced to 2.3 and 0.3 repeats/month in Q140 with Msh3 heterozygous and homozygous alleles, respectively. Our study defines somatic Htt CAG-repeat thresholds below which there are no detectable mHtt nuclear or neuropil aggregates. Mild transcriptionopathy can still occur in Q140 mice with stabilized Htt 140-CAG repeats, but the majority of transcriptomic changes are due to somatic repeat expansion. Our analysis reveals 479 genes with expression levels highly correlated with modal-CAG length in MSNs. Thus, our study mechanistically connects HD GWAS genes to selective neuronal vulnerability in HD, in which Msh3 and Pms1 set the linear rate of neuronal mHtt CAG-repeat migration to drive repeat-length dependent pathogenesis; and provides a preclinical platform for targeting these genes for HD suppression across brain regions. One Sentence SummaryMsh3 and Pms1 are genetic drivers of sequential striatal and cortical pathogenesis in Q140 mice by mediating selective CAG-repeat migration in HD vulnerable neurons.

neuroscience↗