Biology subjects

McDonough, J.

Publications and source records attributed to McDonough, J..

7 recordsLinked to original sources

bioRxiv2026

The BHMT-TET1 axis regulates glycolytic metabolism in oligodendrocytes and increases myelin in the EAE mouse model of multiple sclerosis

The inability of oligodendrocyte progenitor cells (OPCs) to mature into myelin-making oligodendrocytes (OLs) is a major contributor to disease and disability in multiple sclerosis (MS). Oligodendrocyte maturation is a tightly controlled process with a strong reliance on epigenetic regulation involving DNA methylation and hydroxymethylation. We have previously shown that one carbon metabolism is dysregulated in MS, specifically the methyl donor betaine is depleted in the MS brain. Betaine donates methyl groups to betaine homocysteine methyltransferase (BHMT) in the methionine cycle to increase S-adenosylmethionine (SAM) for epigenetic methylation processes. In the present study we tested the effects of activating the BHMT methylation pathway on preventing MS pathology. We describe a novel mechanism mediated by BHMT and the Ten-eleven translocator enzyme (TET1) that converts 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC). We show that this pathway supports oligodendrocyte metabolism to enhance myelin and reduce clinical disability in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. ChIP-seq studies show that BHMT is enriched at genes involved in OPC metabolism and proximal ligation assays (PLAs) demonstrate that BHMT interacts with TET1 on chromatin. This interaction regulates gene expression programs that support a shift in OPC metabolism to glycolysis during neuroinflammatory processes. These data highlight the critical role of methionine metabolism in supporting myelination and have important implications for the development of new therapeutic strategies for MS and other neurodegenerative diseases.

neuroscience↗

bioRxiv2026

A Denisovan-derived Alu insertion in OCA2 contributes to pigmentation diversity in present-day Melanesians

Modern humans inherited DNA from Neanderthals and Denisovans, but the contribution of introgressed structural variants (SVs) to present-day human phenotypes and adaptation remains poorly understood. Here, we used a graph-genome approach to genotype 96,277 SVs in 3,332 present-day humans and three high-coverage archaic hominin genomes, identifying 153 candidate introgressed SVs. These SVs are enriched for signatures of local adaptation compared to non-introgressed SVs (p-value = 3.04 x 10-7). Among these, we focused on a Denisovan-derived Alu insertion located in intron 18 of OCA2, a gene central to pigmentation. This introgressed Alu insertion is most frequently observed (> 60%) in Indigenous people from Bougainville Island of Melanesia, and is significantly associated with increased skin pigmentation in this region. To assess its functional impact, the Alu insertion was introduced into human induced pluripotent stem cells (iPSCs), which were subsequently differentiated into melanocytes. Melanocytes harboring the Alu insertion demonstrated elevated OCA2 expression, increased pigmentation, and higher levels of enhancer activity compared to controls. Collectively, these findings highlight introgressed SVs as a significant source of adaptive and phenotypic diversity in modern humans and implicate the Denisovan-derived Alu insertion in OCA2 in pigmentation variation among present-day Melanesian populations.

genomics↗

bioRxiv2026

Embryonic environment impacts adult traits and phenotypic integration in the pea aphid

Understanding how the embryonic environment affects adult phenotype is critical in the context of both human health and the increasing variance of environmental conditions due to climate change. Here we consider this topic within the framework of phenotypic integration, i.e., the pattern of correlations among elements of functionally robust trait suites. We investigated the life-long consequences of alternative embryonic environments on phenotypic integration in the pea aphid (Acyrthosiphon pisum). We exposed live-bearing pea aphid mothers to an adverse, high-density environment or a benign, low-density environment and measured morphological traits, fecundity, and transcriptional profiles in the resulting winged and wingless adult offspring. We observe that morphological integration decreases in both morphs in response to the adverse maternal environment. Transcriptional integration, on the other hand, shows a morph-specific response: integration increases in wingless offspring but decreases in winged offspring in response to the adverse maternal environment. Our results show the remarkable phenotypic diversity that a single genotype can express in response to environmental variation; that maternal environmental conditions can have strong effects on offspring trait variation and trait integration; and that these effects differ at the morphological and transcriptional levels.

evolutionary biology↗

bioRxiv2024

Virtual Growing Child (VGC): A general normative comparative system via quantitative dynamic MRI for quantifying pediatric regional respiratory anomalies with application in thoracic insufficiency syndrome (TIS)

BackgroundA normative database of regional respiratory structure and function in healthy children does not exist. MethodsVGC provides a database with four categories of regional respiratory measurement parameters including morphological, architectural, dynamic, and developmental. The database has 3,820 3D segmentations (around 100,000 2D slices with segmentations). Age and gender group analysis and comparisons for healthy children were performed using those parameters via two-sided t-testing to compare mean measurements, for left and right sides at end-inspiration (EI) and end-expiration (EE), for different age and gender specific groups. We also apply VGC measurements for comparison with TIS patients via an extrapolation approach to estimate the association between measurement and age via a linear model and to predict measurements for TIS patients. Furthermore, we check the Mahalanobis distance between TIS patients and healthy children of corresponding age. FindingsThe difference between male and female groups (10-12 years) behave differently from that in other age groups which is consistent with physiology/natural growth behavior related to adolescence with higher right lung and right diaphragm tidal volumes for females(p<0.05). The comparison of TIS patients before and after surgery show that the right and left components are not symmetrical, and the left side diaphragm height and tidal volume has been significantly improved after surgery (p <0.05). The left lung volume at EE, and left diaphragm height at EI of TIS patients after surgery are closer to the normal children with a significant smaller Mahalanobis distance (MD) after surgery (p<0.05). InterpretationThe VGC system can serve as a reference standard to quantify regional respiratory abnormalities on dMRI in young patients with various respiratory conditions and facilitate treatment planning and response assessment. FundingThe grant R01HL150147 from the National Institutes of Health (PI Udupa).

bioengineering↗

bioRxiv2023

Changes to Astrocyte-associated Protein Expression at Different Timepoints of Cuprizone Treatment

Glial cells, including astrocytes, microglia, and oligodendrocytes, are brain cells that support and dynamically interact with neurons and each other. These intercellular dynamics undergo changes during stress and disease states. In response to most forms of stress, astrocytes will undergo some variation of activation, meaning upregulation in certain proteins expressed and secreted and either upregulations or downregulations to various constitutive and normal functions. While types of activation are many and contingent on the particular disturbance that triggers these changes, there are two main overarching categories that have been delineated thus far: A1 and A2. Named in the convention of microglial activation subtypes, and with the acknowledgement that the types are not completely distinct or completely comprehensive, the A1 subtype is generically associated with toxic and pro-inflammatory factors, and the A2 phenotype is broadly associated with anti-inflammatory and neurogenic factors. The present study served to measure and document dynamic changes in these subtypes at multiple timepoints using an established experimental model of cuprizone toxic demyelination. The authors found increases in proteins associated with both cell types at different timepoints, with protein increases in the A1 marker C3d and the A2 marker Emp1 in the cortex at one week and protein increases in Emp1 in the corpus callosum at three days and four weeks. There were also increases in Emp1 staining specifically colocalized with astrocyte staining in the corpus callosum at the same timepoints as the protein increases, and in the cortex weeks later at four weeks. C3d colocalization with astrocytes also increased most at four weeks. This indicates simultaneous increases of both types of activation as well as the likely existence of astrocytes expressing both markers. The authors also found the increase in two A1 associated proteins (TNF alpha and C3d) did not show a linear relationship in line with findings from other research and indicating a more complex relationship between cuprizone toxicity and astrocyte activation. The increases in TNF alpha and IFN gamma did not occur at timepoints preceding increases in C3d and Emp1, showing that other factors also precipitate the subtypes associated (A1 for C3d and A2 for Emp1). These findings add to the body of research showing the specific early timepoints at which A1 and A2 markers are most increased during the course of cuprizone treatment, including the fact that these increases can be non-linear in the case of Emp1. This provides additional information on optimal times for targeted interventions during the cuprizone model.

neuroscience↗

bioRxiv2020

The Wnt effector TCF7l2 promotes oligodendroglial differentiation by repressing autocrine BMP4-mediated signaling

Promoting oligodendrocyte differentiation represents a promising option for remyelination therapy for treating the demyelinating disease multiple sclerosis (MS). The Wnt effector TCF7l2 was upregulated in MS lesions and had been proposed to inhibit oligodendrocyte differentiation. Recent data suggest the opposite yet underlying mechanisms remain elusive. Here we unravel a previously unappreciated function of TCF7l2 in controlling autocrine bone morphogenetic protein (BMP4)-mediated signaling. Disrupting TCF7l2 results in oligodendroglial-specific BMP4 upregulation and canonical BMP4 signaling activation in vivo. Mechanistically, TCF7l2 binds to Bmp4 gene regulatory element and directly represses its transcriptional activity. Functionally, enforced TCF7l2 expression promotes oligodendrocyte differentiation by reducing autocrine BMP4 secretion and dampening BMP4 signaling. Importantly, compound genetic disruption demonstrates that oligodendroglial-specific BMP4 deletion rescues arrested oligodendrocyte differentiation elicited by TCF7l2 disruption in vivo. Collectively, our study reveals a novel connection between TCF7l2 and BMP4 in oligodendroglial lineage and provides new insights into augmenting TCF7l2 for promoting remyelination in demyelinating disorders such as MS. Significance StatementIncomplete or failed myelin repairs, primarily resulting from the arrested differentiation of myelin-forming oligodendrocytes from oligodendroglial progenitor cells, is one of the major reasons for neurological progression in people affected by multiple sclerosis (MS). Using in vitro culture systems and in vivo animal models, this study unraveled a previously unrecognized autocrine regulation of BMP4-mediated signaling by the Wnt effector TCF7l2. We showed for the first time that TCF7l2 promotes oligodendroglial differentiation by repressing BMP4-mediated activity, which is dysregulated in MS lesions. Our study suggests that elevating TCF7l2 expression may be possible in overcoming arrested oligodendroglial differentiation as observed in MS patients.

neuroscience↗

bioRxiv2020

NAT8L mRNA oxidation is linked to neurodegeneration in multiple sclerosis

RNA oxidation has been implicated in neurodegeneration, but the underlying mechanism for such effects is unclear. Recently, we demonstrated extensive RNA oxidation within the neurons in multiple sclerosis (MS) brain. In this report we identified selectively oxidized mRNAs in neuronal cells that pertained to neuropathological pathways. N-acetyl aspartate transferase 8 like (NAT8L) mRNA is one such transcript, whose translated product enzymatically synthesizes N-acetyl aspartic acid (NAA), a neuronal metabolite important for myelin synthesis. We reasoned that impediment of translation of an oxidized NAT8L mRNA will result in reduction in its cognate protein, thus lowering NAA level. This assertion is directly supported by our studies on a model cellular system, an MS animal model and postmortem human MS brain. Reduced NAA level in the brain hampers myelin integrity making neuronal axons more susceptible to damage, which contributes in MS neurodegeneration. Overall, this work provides a framework for mechanistic understanding of the link between RNA oxidation and neurodegenerative diseases.

molecular biology↗