Biology subjects

McDonough, H.

Publications and source records attributed to McDonough, H..

3 recordsLinked to original sources

bioRxiv2024

predicTTE: An accessible and optimal tool for time-to-event prediction in neurological diseases

Time-to-event prediction is a key task for biological discovery, experimental medicine, and clinical care. This is particularly true for neurological diseases where development of reliable biomarkers is often limited by difficulty visualising and sampling relevant cell and molecular pathobiology. To date, much work has relied on Cox regression because of ease-of-use, despite evidence that this model includes incorrect assumptions. We have implemented a set of deep learning and spline models for time-to-event modelling within a fully customizable app and accompanying online portal, both of which can be used for any time-to-event analysis in any disease by a non-expert user. Our online portal includes capacity for end-users including patients, Neurology clinicians, and researchers, to access and perform predictions using a trained model, and to contribute new data for model improvement, all within a data-secure environment. We demonstrate a pipeline for use of our app with three use-cases including imputation of missing data, hyperparameter tuning, model training and independent validation. We show that predictions are optimal for use in downstream applications such as genetic discovery, biomarker interpretation, and personalised choice of medication. We demonstrate the efficiency of an ensemble configuration, including focused training of a deep learning model. We have optimised a pipeline for imputation of missing data in combination with time-to-event prediction models. Overall, we provide a powerful and accessible tool to develop, access and share time-to-event prediction models; all software and tutorials are available at www.predictte.org.

neuroscience↗

bioRxiv2018

Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of cerebellar CHIPopathy

CHIP (carboxyl terminus of heat shock 70-interacting protein) has long been recognized as an active member of the cellular protein quality control system given the ability of CHIP to function as both a co-chaperone and ubiquitin ligase. Mutations in CHIP are the driver of spinocerebellar autosomal recessive 16 (SCAR16), or cerebellar CHIPopathy, as we initially discovered this disease was caused by a loss of CHIP ubiquitin ligase function. The initial mutation describing SCAR16 was a missense mutation in the ubiquitin ligase domain of CHIP (p.T246M). Using multiple biophysical and cellular approaches, we demonstrate that T246M mutation results in structural disorganization and misfolding of the CHIP U-box domain, promoting oligomerization, and increased proteasome-dependent turnover. CHIP-T246M has no ligase activity, but maintains interactions with chaperones and alters the co-chaperone function of CHIP. To establish preclinical models of SCAR16, we engineered T246M at the endogenous locus in both mice and rats. Animals homozygous for T246M had both cognitive and motor cerebellar dysfunction distinct from those observed in the CHIP null animal model, as well as deficits in learning and memory, reflective of the cognitive deficits reported in SCAR16 patients. We conclude that the T246M mutation is not equivalent to the total loss of CHIP, supporting the concept that disease-causing CHIP mutations have different biophysical and functional repercussions on CHIP function that may directly correlate to the spectrum of clinical phenotypes observed in SCAR16 patients. Our findings both further expand our basic understanding of CHIP biology and provide meaningful mechanistic insight underlying the molecular drivers of SCAR16 disease pathology, which may be used to inform the development of novel therapeutics for this devastating disease.

animal behavior and cognition↗

bioRxiv2017

Loss of CHIP Expression Perturbs Glucose Homeostasis and Leads to Type II Diabetes through Defects in Microtubule Polymerization and Glucose Transporter Localization

Recent evidence has implicated CHIP (carboxyl terminus of Hsc/Hsp70-interacting protein), a co-chaperone and ubiquitin ligase, in the functional support of several metabolism-related proteins, including AMPK and SirT6. In addition to previously reported aging and stress intolerance phenotypes, we find that CHIP -/- mice also demonstrate a Type II diabetes-like phenotype, including poor glucose tolerance, decreased sensitivity to insulin, and decreased insulin-stimulated glucose uptake in isolated skeletal muscle, characteristic of insulin resistance. In CHIP-deficient cells, glucose stimulation fails to induce translocation of Glut4 to the plasma membrane. This impairment in Glut4 translocation in CHIP-deficient cells is accompanied by decreased tubulin polymerization associated with decreased phosphorylation of stathmin, a microtubule-associated protein required for polymerization-dependent protein trafficking within the cell. Together, these data describe a novel role for CHIP in regulating microtubule polymerization that assists in glucose transporter translocation, promoting whole-body glucose homeostasis and sensitivity to insulin.

physiology↗