Biology subjects

Tejeda, G. S.

Publications and source records attributed to Tejeda, G. S..

5 recordsLinked to original sources

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↗

bioRxiv2024

Interactions established by isoform-specific TrkB-T1 sequences govern inflammatory response and neurotoxicity in stroke

Ugalde-Trivino et al. develop cell-penetrating peptides derived from neurotrophin receptor TrkB-T1 to identify isoform-specific protein interactions and demonstrate protective effects on neuroinflammation and neurotoxicity reducing brain damage in a mice model of ischemic stroke, of relevance to human therapy. AbstractGlia reactivity, neuroinflammation and excitotoxic neuronal death are central processes to ischemic stroke and neurodegenerative diseases, altogether a leading cause of death, disability, and dementia. Due to the high incidence of these pathologies and the lack of efficient treatments, it is a priority developing brain protective therapies impacting both neurons and glial cells. Truncated neurotrophin receptor TrkB-T1, a protein produced by all these cells, plays relevant roles in excitotoxicity and ischemia. We have hypothesized that interactions established by isoform-specific TrkB-T1 sequences might be relevant to neurotoxicity and/or reactive gliosis and, therefore, constitute a therapeutic target. We identify here the TrkB-T1-specific interactome, poorly described to date, and demonstrate that interference of these protein-protein interactions using brain-accessible TrkB-T1-derived peptides can prevent reactive gliosis and decrease excitotoxicity-induced damage in cellular and mouse models of stroke. The pivotal role played by TrkB-T1 on microglia and astrocyte reactivity suggests that isoform-derived peptides could become important in development of therapies for human stroke and other excitotoxicity-associated pathologies.

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

Validation of the Early Warning and Response System (EWARS) for dengue outbreaks: Evidence from the national vector control program in Mexico

BackgroundDuring 2017, twenty health districts (locations) in Mexico implemented a dengue outbreak early warning and response system (EWARS) that uses epidemiological, meteorological and entomological variables (alarm indicators) to predict dengue outbreaks and triggers early response activities. Eleven of these districts were analyzed as they presented reliable information. Nine districts presented outbreak alarms but without subsequent outbreaks ("non-outbreak districts") and two presented after the alarms dengue outbreaks ("outbreak districts"). This study is concerned with i) if the alarms without outbreaks were false alarms or if the control services had established effective response activities averting an outbreak and ii) if vector control activities can mitigate or even avert dengue outbreaks. MethodsFive components of dengue outbreak response (larval control, entomological studies with water container interventions, focal spraying, indoor residual spraying, space spraying) were quantitatively analyzed across two groups ("outbreak districts" and "non-outbreak districts"). ResultsThe average coverage of vector control and responses were higher in non-outbreak districts and across all five components. In the "outbreak districts" the response activities started late and were of much lower intensity compared to "non-outbreak districts". District vector control teams demonstrated diverse compliance with local guidlines for initial, early and late responses to outbreak alarms which could explain the different outcomes observed following the outbreak alarms. Conclusionfindings from this study plausibly demonstrates important operational scenarios when succeeding or failing alarms signals generated by EWARS at national level. This study presents evidence warranting for further investigation into the effectiveness and cost-effectiveness of EWARS using gold-standard designs.

scientific communication and education↗

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↗