Biology subjects

Reis, P. M.

Publications and source records attributed to Reis, P. M..

3 recordsLinked to original sources

bioRxiv2026

Adaptation of α-synuclein fibrils following multiple system atrophy transmission to mice

Synucleinopathies are a group of neurodegenerative diseases characterized by the presence of misfolded -synuclein inclusions which cause progressive disease by spreading throughout the brain in a prion-like manner. Throughout the neurodegenerative disease field, the ability of a single protein to give rise to multiple distinct clinical disorders is explained by the strain hypothesis, or the idea that the misfolded protein conformation determines the resulting disease. This was initially shown using transmission studies in cell lines and mouse models; more recently cryo-electron microscopy (cryo-EM) validated this idea by identifying distinct -synuclein filament folds in brain tissues from patients with Parkinsons disease, multiple system atrophy (MSA), and juvenile-onset synucleinopathy. However, very little is known about the -synuclein filament structures that form in animal models of these disorders, and thus their relevance to human disease and suitability as models for therapeutic development remains a question. Here we report the first atomic resolution cryo-EM structures of -synuclein fibrils from an MSA patient sample before and after transmission to a transgenic mouse model of disease. Our findings indicate that while distinct adaptations occur during fibril replication in the mouse host, key structural facets are maintained, validating the merits of this transmission model for supporting preclinical research on MSA.

neuroscience↗

bioRxiv2025

Impact of chronic alcohol and stress on mid-life cognition and locus coeruleus integrity

BackgroundExcessive alcohol consumption and stress are associated with structural and functional alterations in the brain and impaired cognition. However, the persistence of long-term neural impacts after alcohol and stress are less understood. This study investigated midlife cognition and neuropathological changes following a history of alcohol and stress exposure. MethodsC57BL/6J mice acclimated to ethanol drinking (15% v/v) before exposure to four cycles of alternating chronic intermittent ethanol (CIE) vapor exposure and repeated forced swim stress (FSS), with control groups exposed to air and no stress (AIR/NS). After three months of abstinence, mice were evaluated at midlife (11 months old) on volitional drinking and a final CIE/FSS challenge for stress induced drinking. Spatial learning and cognitive flexibility were assessed using the Barnes maze before brains were collected to evaluate locus coeruleus integrity at 12 months old. ResultsCIE/FSS increased volitional alcohol intake, and this drinking phenotype persisted through to midlife despite extended abstinence. CIE/FSS mice showed intact spatial learning but impaired flexibility in the Barnes maze reversal phase. Flexibility impairments were driven by decreased time in the target quadrant and increased errors during the reversal test compared to AIR/NS. Furthermore, CIE/FSS mice showed pathological measures of reduced locus coeruleus integrity common to dementia related disorders, including elevated markers of oxidative stress, apoptosis and reduced autoinhibitory function. ConclusionsOur findings highlight the long-lasting impact of alcohol and stress exposure on cognition, with flexibility impairments persisting into midlife. In addition to cognitive changes, alcohol and stress history produced pathological changes in the locus coeruleus, an area known to mediate cognitive flexibility via its forebrain projections. Together, these results give an insight into the long-lasting impacts of chronic alcohol and stress and how they may accelerate age-related cognitive decline.

neuroscience↗

bioRxiv2024

Structurally targeted mutagenesis identifies key residues supporting α-synuclein misfolding in multiple system atrophy

Multiple system atrophy (MSA) and Parkinsons disease (PD) are caused by misfolded -synuclein spreading throughout the central nervous system. While familial PD is linked to several point mutations in -synuclein, there are no known mutations associated with MSA. Our previous work investigating differences in -synuclein misfolding between the two disorders showed that the familial PD mutation E46K inhibits replication of MSA prions both in vitro and in vivo, providing key evidence to support the hypothesis that -synuclein adopts unique strains in patients. Here, to further interrogate -synuclein misfolding, we engineered a panel of cell lines harboring both PD-linked and novel mutations designed to identify key residues that facilitate -synuclein misfolding in MSA. These data were paired with in silico analyses using Maestro software to predict the effect of each mutation on the ability of -synuclein to misfold into one of the reported MSA cryo-electron microscopy conformations. In many cases, our modeling accurately identified mutations that facilitated or inhibited MSA replication. However, Maestro was occasionally unable to predict the effect of a mutation on MSA propagation in vitro, demonstrating the challenge of using computational tools to investigate intrinsically disordered proteins. Finally, we used our cellular models to determine the mechanism underlying the E46K-driven inhibition of MSA replication, finding that the E46/K80 salt bridge is necessary to support -synuclein misfolding. Overall, our studies use a structure-based approach to investigate -synuclein misfolding, resulting in the creation of a powerful panel of cell lines that can be used to interrogate MSA strain biology.

neuroscience↗