Biology subjects

Williams, M. T.

Publications and source records attributed to Williams, M. T..

8 recordsLinked to original sources

bioRxiv2026

Proteome-wide QTL mapping enables gene-protein-phenotype metabolic network construction in a genetically diverse MASLD mouse model

The limited treatment options available for the estimated 38% of adults worldwide affected by Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) are largely due to an incomplete understanding of the complex molecular networks underlying disease pathogenesis. To dissect the genetic architecture and proteomic regulation underlying MASLD, we generated a genetically diverse mouse cohort through a four-way cross of founder strains with varying susceptibility to liver disease, producing 444 F2 mice with a spectrum of phenotypes and genotypes. Utilizing deep proteomic profiling of the livers of this population, we identified quantitative trait loci (QTL) for 2,652 proteins, spanning over 4,000 unique genomic loci, and distinguished cis- and trans-acting regulatory mechanisms. Integrating proteomic, genomic, and phenotypic data reveals key regulatory loci and candidate proteins influencing disease progression, creating a mineable proteogenomic resource for MASLD research. We utilize this resource to identify the E3 ubiquitin ligase Ubr1 as a candidate central regulator connecting proteostasis and lipid metabolism, with genetic polymorphisms that may alter its abundance and predispose to metabolic dysfunction. This study demonstrates how high-throughput, deep proteome profiling integrated with QTL mapping can reveal complex gene-protein networks governing MASLD susceptibility and progression, offering novel insights for biomarker discovery and therapeutic targeting.

systems biology↗

bioRxiv2026

LIMK Inhibition and Metformin Block Mitochondrial Transfer Overcoming Macrophage Driven Therapy Resistance in Acute Myeloid Leukaemia

Chemoresistance is a major contributor to poor clinical outcomes in AML patients and can arise from interactions between AML cells and the bone marrow microenvironment (BME). How immune cells, particularly macrophages (M{varphi}s), facilitate this process requires better clarification. This study shows that M2-like M{varphi}s protect AML cells from apoptosis induced by daunorubicin (DNR) and cytarabine (Ara-C). This protection occurs via co-culture and is linked to enhanced mitochondrial transfer from M{varphi}s to AML cells. M{varphi}s interacted with AML cells via tunneling nanotube (TNT)-like structures. Furthermore, inhibition of mitochondrial transfer using cytochalasin B reduced the protective effect, indicating that mitochondria mediate this process. M{varphi}s transferred functional mitochondria to AML cells as evidenced by enhanced metabolic capacity and reduced reactive oxygen species levels in AML cells under chemotherapy stress. TH-257 (LIMK inhibitor) and metformin blocked mitochondrial transfer and M{varphi}-driven chemoprotection. Moreover, increased transcript expression levels of RhoC and cofilin correlate with inferior overall survival in AML patients. These findings suggest that M2-like M{varphi}s contribute to chemoresistance through TNT-mediated mitochondrial transfer and the LIMK-Cofilin pathway, identifying potential therapeutic targets to circumvent chemoresistance in AML.

cancer biology↗

bioRxiv2025

Genetic activation of ERK2 recapitulates core neurodevelopmental features of Rasopathy syndromes in mice

Germline pathogenic variants that activate the Ras/mitogen-activated protein kinase (MAPK) pathway cause neurodevelopmental disorders called Rasopathies. Because many affected proteins directly regulate Ras, causative mutations may alter other Ras-dependent pathways in addition to MAPK signaling. To better understand which Rasopathy sequelae result from hyperactivation of downstream MAP kinases, we engineered mice with a gain-of-function mutation in the terminal MAP kinase gene Mapk1, which encodes ERK2 and is associated with the recently described genetic syndrome MAPK1-related Rasopathy (MRR). Mapk1 mutant mice successfully modeled key aspects of the human MRR phenotype, including small stature, facial dysmorphism, and impaired cognitive function. Importantly, they recapitulated phenotypes identified in Rasopathy models with upstream Ras activation, such as neurofibromatosis type 1 (NF1): oligodendrocyte lineage defects, reactive astrogliosis, memory deficits, and hypersensitivity to sensory stimuli. These findings emphasize the importance of downstream MAPK signaling in the pathophysiology of neurocognitive symptoms observed in Rasopathy syndromes.

genetics↗

bioRxiv2025

Olfactory dysfunction in a novel model of prodromal Parkinson's disease in adult zebrafish

Olfactory dysfunction is an early clinical marker of prodromal Parkinsons disease (PD), yet the underlying mechanisms remain unclear. To explore this relationship, we developed a zebrafish model that recapitulates prodromal PD-associated olfactory impairment without affecting motor function. We used zebrafish, due to their olfactory systems similarity to mammals and their unique nervous system regenerative capacity. By injecting 6-hydroxydopamine (6-OHDA) into the dorsal telencephalic ventricle, we observed a significant loss of dopaminergic (DA) periglomerular neurons in the olfactory bulb (OB) and retrograde degeneration of olfactory sensory neurons (OSNs) in the olfactory epithelium (OE). These alterations led to impaired responses to cadaverine, an aversive odorant, while responses to alanine, an attractive odorant, remained intact. 6-OHDA triggered robust neuroinflammatory responses that was attenuated by pranlukast, an anti-inflammatory drug. By 7 days post-injection, dopaminergic synapses in the OB were remodeled, OSNs in the OE appeared recovered, and neuroinflammation subsided, leading to full recovery of olfactory responses to cadaverine. These findings highlight zebrafish remarkable neuroplasticity and suggest this novel model of prodromal PD could provide valuable insights into early PD pathology. Understanding the interplay between dopaminergic loss, neuroinflammation, and olfactory dysfunction may inform therapeutic strategies for PD patients suffering from olfactory dysfunction.

neuroscience↗

bioRxiv2024

Latrophilin-3 conditional knockout in tyrosine hydroxylase neurons (Lphn3-Th-Cre) compared with Lphn3 global KO rats: Role of Lphn3 in tyrosine hydroxylase neurons on cognitive and behavioral effects of this ADHD susceptibility gene

Latrophilin-3 (LPHN3) is a brain specific adhesion G-protein coupled receptor associated with elevated risk of attention deficit hyperactivity disorder (ADHD). We developed a global Lphn3 knock-out (gKO) rat using CRISPR/Cas9 to delete exon-3. Here we report the development of a floxed Lphn3 rat crossed with tyrosine hydroxylase (Th-Cre) rats to create a conditional Lphn3 KO rat specific for catecholaminergic- positive cells. The gKO rats are hyperactive and have egocentric and allocentric navigation deficits but showed sparing of conditioned contextual and novel object recognition memory. Here we compared gKO and cKO rats controlling for litter effects. Both gKO and cKO rats were hyperactive and were impaired in egocentric navigation in the Cincinnati water maze (CWM) with deficits greater in gKO rats. The gKO rats were impaired in allocentric navigation in the Morris water maze (MWM) whereas cKO rats were only slightly affected compared with WT, cre, and floxed rats. Striatal tyrosine hydroxylase and dopamine D1 receptors were not significantly different in either model, nor were NMDA-NR1 or NMDA-NR2 in the hippocampus. We previously showed, however, that dopamine is released more rapidly in the striatum of gKO rats by fast- scan cyclic voltammetry. The cKO model shows an important role of catecholamines in the phenotype of LPHN3 disruption and add evidence that this synaptic protein plays a role in neuroplasticity that are consistent with ADHD.

neuroscience↗

bioRxiv2022

Temporal interference current stimulation in peripheral nerves

One strategy to electrically stimulate nerves utilizes the interference of multiple high frequency waveforms. This technique has recently gained significant attention as a method to improve the state-of-the-art in neurostimulation. Here we report our investigation into the fundamental properties of the neuronal response to these types of waveforms. Our data suggest, contrary to the currently accepted explanation, that neurons do not extract envelopes at all, and that the response to these signals is well explained by a resistor-capacitor (i.e., integrator) membrane with a fixed firing threshold. This new understanding of the fundamental mechanism of interferential neural stimulation changes how we should model and evaluate the safety and efficacy of these signals. Utilizing this new understanding, we develop several novel interferential stimulation techniques. Interferential strategies demonstrate promising results and may improve many neuromodulation therapies.

bioengineering↗

bioRxiv2020

Prenatal psychosocial stress-induced behavioral and neuroendocrine abnormalities are associated with sex-specific alterations in synaptic transmission and differentially modulated by maternal environment

Prenatal stress (PS) is associated with increased vulnerability to affective disorders. Transplacental glucocorticoid passage and stress-induced maternal environment alterations are recognized as potential routes of transmission that can fundamentally alter neurodevelopment. However, molecular mechanisms underlying aberrant emotional outcomes or the individual contributions intrauterine stress versus maternal environment play in shaping these mechanisms remain unknown. Here, we report anxiogenic behaviors, anhedonia, and female hypothalamic-pituitary-adrenal axis hyperactivity as a consequence of psychosocial PS in mice. Sex-specific placental responses to stress and evidence of fetal amygdala programming precede these abnormalities. In adult offspring, we observe amygdalar transcriptional changes demonstrating sex-specific dysfunction in synaptic transmission and neurotransmitter systems. We find these abnormalities are primarily driven by in-utero stress exposure. Importantly, maternal care changes postnatally reverse anxiety-related behaviors and partially rescue gene alterations associated with neurotransmission. Our data demonstrate the influence maternal environment exerts in shaping offspring emotional development despite deleterious effects of intrauterine stress.

neuroscience↗

bioRxiv2017

Cognitive deficits and increases in creatine precursors in a brain-specific knockout of the creatine transporter gene Slc6a8

Creatine transporter (CrT; SLC6A8) deficiency (CTD) is an X-linked disorder characterized by severe cognitive deficits, impairments in language, and an absence of brain creatine (Cr). In a previous study, we generated floxed Slc6a8 (Slc6a8flox) mice to create ubiquitous Slc6a8 knockout (Slc6a8-/y) mice. Slc6a8-/y mice lacked whole body Cr and exhibited cognitive deficits. While Slc6a8-/y mice have a similar biochemical phenotype to CTD patients, they also showed a reduction in size and reductions in swim speed that may have contributed to the observed deficits. To address this, we created brain-specific Slc6a8 knockout (bKO) mice by crossing Slc6a8Flox mice with Nestin-cre mice. bKO mice had reduced cerebral Cr levels while maintaining normal Cr levels in peripheral tissue. Interestingly, brain concentrations of the Cr synthesis precursor guanidinoacetic acid were increased in bKO mice. bKO mice had longer latencies and path lengths in the Morris water maze, without reductions in swim speed. In accordance with data from Slc6a8-/y mice, bKO mice showed deficits in novel object recognition as well as contextual and cued fear conditioning. bKO mice were also hyperactive, in contrast with data from the Slc6a8-/y mice. The results demonstrate that the loss of cerebral Cr is responsible for the learning and memory deficits seen in ubiquitous Slc6a8-/y mice.

neuroscience↗