Biology subjects

McFall, A.

Publications and source records attributed to McFall, A..

3 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↗

bioRxiv2024

Polyolefin colonization and partial degradation by Gordonia sp., and Arthrobacter sp. isolated from wetlands and compost

Plastics and microplastics constitute an ever-increasing pollutant in the biosphere. There is clear evidence that environmental microbes possess enzyme systems and metabolic apparatus to degrade natural high molecular weight polymers, which substantially overlap with those involved in the biodegradation of plastics. This study investigated the presence and activities of plastic-degrading microbes in environments with a high abundance of plant-derived polymers, including cellulosic, chitinous, or lignin-derived compounds. Microbes were enriched in a minimal medium, with low-density polyethylene (LDPE), polypropylene (PP), poly(ethylene terephthalate) (PET), or polystyrene (PS) as the sole carbon source, resulting in 12 bacterial isolates. Plastic mass loss and cell viability were measured over a 28-day incubation period, in addition to assessment of biofilm formation. Gordonia sp. iso11 displayed mass loss of PP of up to 22.8% and formed a viable dense biofilm (109 CFU cm-2) on a PP film. A putative alkane-1-monoxygenase (AlkB) was identified from genome sequence analysis, which aligned with a known LDPE-degrading enzyme. Furthermore, reductions in the contact angle of medium supernatant from Gordonia sp. iso11 provided evidence of biosurfactant production which may enhance the bioavailability of the synthetic plastic. To our knowledge, this is the first demonstration of PP degradation by Gordonia.

microbiology↗

bioRxiv2020

Phosphodiesterase Type 4 anchoring regulates cAMP signaling to Popeye domain-containing proteins.

Cyclic AMP is a ubiquitous second messenger used to transduce intracellular signals from a variety of Gs-coupled receptors. Compartmentalisation of protein intermediates within the cAMP signaling pathway underpins receptor-specific responses. The cAMP effector proteins protein-kinase A and EPAC are found in complexes that also contain phosphodiesterases whose presence ensures a coordinated cellular response to receptor activation events. Popeye proteins are the most recent class of cAMP effectors to be identified and have crucial roles in cardiac pacemaking and conduction. We report the first observation that Popeye proteins exist in complexes with members of the PDE4 family in cardiac myocytes thus restricting cAMP signaling. We show that POPDC1 preferentially binds the PDE4A sub-family via a specificity motif in the PDE4 UCR1 region and that PDE4s bind to the Popeye domain of POPDC1 in a region known to be susceptible to a mutation that causes human disease. Using a cell-permeable disruptor peptide that displaces the POPDC1-PDE4 complex we show that PDE4 activity localized to POPDC1 is essential to maintain action potential duration in beating cardiac myocytes.

biochemistry↗