Biology subjects

Molloy, C.

Publications and source records attributed to Molloy, C..

7 recordsLinked to original sources

bioRxiv2026

The importance of M1 muscarinic receptor phosphorylation in learning and memory

The muscarinic acetylcholine receptor 1 (mAChR1, M1) has been identified as a primary target for Alzheimers disease (AD) and better understanding of the receptor biology, especially in regard to biased signalling of the receptor, will allow for the development of improved drugs targeting cholinergic dysfunction in AD. The aim of this study was to determine the contribution of phosphorylation of M1 to the learning and memory (LM) effects of M1 agonism. The contribution of M1 phosphorylation dependent signalling in LM was assessed using the mAChR1 positive allosteric modulator, VU0486846, in a scopolamine (1.5 mg/kg) induced LM deficit model in mice expressing HA-tagged M1 (M1-WT), phosphorylation deficient HA-tagged M1 (M1-PD), or mice deficient in M1 (M1-KO). LM was assessed using a fear conditioning (FC) testing paradigm where context and cued memory retrieval was measured 24 hrs after training and a higher level of freezing indicated intact memory. Results demonstrated that scopolamine induced a significant LM deficit in both context and cued retrieval in M1-WT mice which was partially rescued by VU0486846 confirming a contribution of M1 signalling in LM. The scopolamine induced deficit in contextual retrieval in M1-KO mice was not rescued by VU0486846, which is an M1 selective ligand, while scopolamine did not induce a deficit in cued retrieval in M1-KO mice. In M1-PD mice, scopolamine induced a LM deficit in contextual retrieval, however this was also not rescued by VU0486846 treatment. Similarly to M1-KO animals, M1-PD mice did not display a scopolamine induced deficit in cued retrieval. When freezing responses were compared across strains, M1-PD mice displayed a deficit compared to M1-WT and M1-KO mice in contextual retrieval, while both M1-PD and M1-KO mice displayed a deficit compared to M1-WT mice in cued retrieval. These results demonstrate that although M1 agonism can restore a LM deficit in both contextual and cued testing paradigms, only the cued retrieval response is dependent on the M1. Additionally, biased Gq M1 signalling is not sufficient to restore contextual memory and requires phosphorylation of the receptor. Furthermore, biased M1 signalling results in LM deficits not seen with KO of the receptor. Overall, these results reiterate the importance of considering the bias of ligands when developing M1 agonists for dementia in the future.

neuroscience↗

bioRxiv2025

Identification of M4 muscarinic acetylcholine receptor expressing astrocytes that regulate locomotion and survival in murine prion disease

Whilst there has been much focus on neuronally expressed muscarinic acetylcholine receptors (mAChRs), less attention has been paid to their expression and role in non-neuronal brain cells. Using genetically engineered mice, we identify a previously unappreciated subpopulation of astrocytes expressing the M4 mAChR subtype dispersed across various regions that include the brainstem, hypothalamus and, most abundantly, the cerebellum. Signalling and proteomic analysis of M4 mAChR positive astrocytes from the cerebellum confirmed functional receptor expression and its role in regulating protein expression. Genetic ablation of these astrocytes in mice revealed a specific role in locomotion. Importantly, in the context of murine prion disease, we observed a significant expansion of M4 mAChR positive astrocytes, and ablation experiments established that this astrocyte subpopulation has a detrimental effect on late-stage disease. Together we identify M4 mAChR expressing astrocyte subpopulation that plays a specific role in normal neurophysiology and the progression of inflammatory neurodegenerative disease.

neuroscience↗

bioRxiv2023

Practice makes imperfect: stronger implicit interference with practice in individuals at high risk of developing Alzheimer's disease

Early screening to determine patient risk of developing Alzheimers will allow better interventions and planning but necessitates accessible methods such as behavioral biomarkers. Previously, we showed that cognitively healthy older individuals whose cerebrospinal fluid amyloid / tau ratio indicates high risk of cognitive decline experienced implicit interference during a high-effort task, signaling early changes in attention. To further investigate attentions effect on implicit interference, we analyzed two experiments completed sequentially by the same high- and low-risk individuals. We hypothesized that if attention modulates interference, practice would affect the influence of implicit distractors. Indeed, while both groups experienced a strong practice effect, the association between practice and interference effects diverged between groups: stronger practice effects correlated with more implicit interference in high-risk participants, but less interference in low-risk individuals. Furthermore, low-risk individuals showed a positive correlation between implicit interference and EEG low-range alpha event-related desynchronization when switching from high-to low-load tasks. These results demonstrate how attention impacts implicit interference and highlight early differences in cognition between high- and low-risk individuals.

neuroscience↗

bioRxiv2021

Activation of M1 muscarinic receptors reduce pathology and slow progression of neurodegenerative disease.

The most prevalent types of dementias, including Alzheimers disease, are those that are propagated via the spread of "prion-like" misfolded proteins. Despite considerable effort no treatments are available to slow or stop the progression of these dementias. Here we investigate the possibility that activation of the M1-muscarinic receptor (M1-receptor), which is highly expressed in the brain and that shows pro-cognitive properties, might present a novel disease modifying target. We demonstrate that the progression of murine prion disease, which we show here displays many of the pathological, behavioural and biochemical hallmarks of human neurodegenerative disease, is slowed and normal behaviour maintained by the activation of the M1-receptor with a highly tolerated positive allosteric modulator (VU846). This correlates with a reduction in both neuroinflammation and indicators of mitochondrial dysregulation, as well as a normalisation in the expression of markers associated with neurodegeneration and Alzheimers disease. Furthermore, VU846 preserves expression of synaptic proteins and post-synaptic signalling components that are altered in disease. We conclude that allosteric regulation of M1-receptors has the potential to reduce the severity of neurodegenerative diseases caused by the prion-like propagation of misfolded protein in a manner that extends life span and maintains normal behaviour.

neuroscience↗

bioRxiv2021

Subtly altered topological asymmetry of brain structural covariance networks in autism spectrum disorder across 43 datasets from the ENIGMA consortium

Small average differences in the left-right asymmetry of cerebral cortical thickness have been reported in individuals with autism spectrum disorder (ASD) compared to typically developing controls. Although these alterations affect multiple and widespread cortical regional asymmetries, the extent to which specific structural networks might be affected remains unknown. Inter-regional morphological covariance analysis can capture network connectivity relations between different cortical areas at the macroscale level. Here, we used cortical thickness data from 1,455 individuals with ASD and 1,560 controls, across 43 independent datasets of the ENIGMA consortiums ASD Working Group, to assess hemispheric asymmetries of intra-individual structural covariance networks, using graph theory-based topological metrics. Compared with typical features of small-world architecture in controls, the ASD sample showed significantly altered asymmetry of hemispheric networks involving the fusiform, rostral middle frontal, and medial orbitofrontal cortex, driven by shifts toward higher randomization of the corresponding right-hemispheric networks in ASD. A network involving the superior frontal cortex showed decreased right-hemisphere randomization. Based on comparisons with meta-analyzed functional neuroimaging data, the altered connectivity asymmetry particularly affected networks that subserve working memory, executive functions, language, reading, and sensorimotor processes. Taken together, these findings provide new insights into how altered brain left-right asymmetry in ASD affects specific structural and functional brain networks. Altered asymmetrical brain development in ASD may be partly propagated among spatially distant regions through structural connectivity.

neuroscience↗

bioRxiv2021

Phosphorylation of the M1 muscarinic acetylcholine receptor mediates protection in neurodegenerative disease

There are currently no treatments that can slow the progression of neurodegenerative diseases such as Alzheimers disease (AD). There is, however, a growing body of evidence that activation of the M1 muscarinic acetylcholine receptor (M1-receptor) can not only restore memory loss in AD patients, but in preclinical animal models can also slow neurodegenerative disease progression. The generation of an effective medicine targeting the M1-receptor has however been severely hampered by associated cholinergic adverse responses. By using genetically engineered mouse models that express a G protein-biased M1-receptor, we recently established that M1-receptor mediated adverse responses can be minimised by ensuring activating ligands maintain receptor phosphorylation/arrestin-dependent signalling. Here, we use these same genetic models in concert with murine prion disease, a terminal neurodegenerative disease showing key hallmarks of AD, to establish that phosphorylation/arrestin-dependent signalling delivers neuroprotection that both extends normal animal behaviour and prolongs the life span of prion diseased mice. Our data point to an important neuroprotective property inherent to the M1-receptor and indicate that next generation M1-receptor ligands designed to drive receptor phosphorylation/arrestin-dependent signalling would potentially show low adverse responses whilst delivering neuroprotection that will slow disease progression.

pharmacology and toxicology↗

bioRxiv2021

High-content screening of coronavirus genes for innate immune suppression revealsenhanced potency of SARS-CoV-2 proteins

Suppression of the host intracellular innate immune system is an essential aspect of viral replication. Here, we developed a suite of medium-throughput high-content cell-based assays to reveal the effect of individual coronavirus proteins on antiviral innate immune pathways. Using these assays, we screened the 196 protein products of seven coronaviruses (SARS-CoV-2, SARS-CoV-1, 229E, NL63, OC43, HKU1 and MERS). This includes a previously unidentified gene in SARS-CoV-2 encoded within the Spike gene. We observe immune-suppressing activity in both known host-suppressing genes (e.g., NSP1, Orf6, NSP3, and NSP5) as well as other coronavirus genes, including the newly identified SARS-CoV-2 protein. Moreover, the genes encoded by SARS-CoV-2 are generally more potent immune suppressors than their homologues from the other coronaviruses. This suite of pathway-based and mechanism-agnostic assays could serve as the basis for rapid in vitro prediction of the pathogenicity of novel viruses based on provision of sequence information alone.

systems biology↗