Biology subjects

Coyle, J.

Publications and source records attributed to Coyle, J..

3 recordsLinked to original sources

bioRxiv2023

A marker chromosome in psychosis identifies glycine decarboxylase (GLDC) as a novel regulator of neuronal and synaptic function in the hippocampus

The biological significance of a small supernumerary marker chromosome that results in dosage alterations to chromosome 9p24.1, including triplication of the GLDC gene encoding glycine decarboxylase, in two patients with psychosis is unclear. In an allelic series of copy number variant mouse models, we identify that triplication of Gldc reduces extracellular glycine levels as determined by optical fluorescence resonance energy transfer (FRET) in dentate gyrus (DG) but not in CA1, suppresses long-term potentiation (LTP) in mPP-DG synapses but not in CA3-CA1 synapses, reduces the activity of biochemical pathways implicated in schizophrenia and mitochondrial bioenergetics, and displays deficits in prepulse inhibition, startle habituation, latent inhibition, working memory, sociability and social preference. Our results thus provide a link between a genomic copy number variation, biochemical, cellular and behavioral phenotypes, and further demonstrate that GLDC negatively regulates long-term synaptic plasticity at specific hippocampal synapses, possibly contributing to the development of neuropsychiatric disorders.

neuroscience↗

bioRxiv2018

Effects of Pathological Mutations on the Prion-Like Polymerisation of MyD88

A novel concept has emerged whereby the higher-order self-assembly of proteins provides a simple and robust mechanism for signal amplification. This appears to be a universal signalling mechanism within the innate immune system, where the recognition of pathogens or danger-associated molecular patterns need to trigger a strong, binary response within cells. Previously, multiple structural studies have been limited to single domains, expressed and assembled at high protein concentrations. We therefore set out to develop new in vitro strategies to characterise the behaviour of full-length proteins at physiological levels. In this study we focus on the adaptor protein MyD88, which contains two domains with different self-assembly properties: a TIR domain that can polymerise similarly to the TIR domain of Mal, and a Death Domain that has been shown to oligomerise with helical symmetry in the Myddosome complex. To visualize the behaviour of full-length MyD88 without purification steps, we use single-molecule fluorescence coupled to eukaryotic cell-free protein expression. These experiments demonstrate that at low protein concentration, only full-length MyD88 forms prion-like polymers. We also demonstrate that the metastability of MyD88 polymerisation creates the perfect binary response required in innate signalling: the system is silenced at normal concentrations but upstream signalling creates a \"seed\" that triggers polymerisation and amplification of the response. These findings pushed us to re-interpret the role of polymerisation in MyD88-related diseases and we studied the impact of disease-associated point mutations L93P, R196C and L252P/L265P at the molecular level. We discovered that all mutations completely block the ability of MyD88 to polymerise. We also confirm that L252P, a gain-of-function mutation, allows the MyD88 mutant to form extremely stable oligomers, even when expressed at low nanomolar concentrations. Thus, our results are consistent with and greatly add to the findings on the Myddosomes digital all-or-none responses and the behaviour of the oncogenic mutation of MyD88.

molecular biology↗

bioRxiv2017

Insights into Hepatitis C Transmission in Young Persons who Inject Drugs: Results From a Dynamic Modeling Approach Informed by State-Level Public Health Surveillance Data

Rising use of heroin and prescription opioids are major contributors to increases in Hepatitis C Virus (HCV) incidence in US young adults since the late 1990s. How best to interrupt transmission and decrease HCV prevalence in young persons who inject drugs (PWID) is uncertain, but modeling studies in older populations support interventions that increase HCV treatment among all PWID. We developed a transmission model of young (aged 15-30 years) PWID, which we fit to state-level US HCV surveillance data, and simulated the potential impact of primary (reducing injection initiation), secondary (increasing cessation, reducing injection partners, or reducing injection drug use relapse), and tertiary (HCV treatment) interventions on incident and prevalent HCV cases. Interventions with primary prevention initiatives (reducing injection initiation) yielded concurrent reductions to HCV incidence and prevalence. Treatment of former PWID led to prevalence reductions but did not reduce incidence. Treatment of current and former PWID without other interventions led to incidence reductions in scenarios with high injection initiation rates, high syringe sharing, and low relapse rates after injection cessation. While these results are specific to Michigan, our approach could be applied in other states conducting HCV surveillance to identify local-level intervention opportunities.

epidemiology↗