Biology subjects

Boehme, B.

Publications and source records attributed to Boehme, B..

3 recordsLinked to original sources

bioRxiv2024

Aggregation promoting sequences rather than phosphorylation are essential for Tau-mediated toxicity in Drosophila

BackgroundDisease-modifying therapies for tauopathies like Alzheimers disease have targeted Tau hyperphosphorylation and aggregation, as both pathological manifestations are implicated in Tau-mediated toxicity. However, the relative contributions of these pathology-linked changes to Tau neurotoxicity remain unclear. MethodsLeveraging the genetic tractability of Drosophila, we generated multiple inducible human Tau transgenes with altered phosphorylation status and/or aggregation propensity. Their individual and combined impact was tested in vivo by quantifying Tau accumulation and neurodegenerative phenotypes in the aging fly nervous system. ResultsWe report that phospho-mimicking Tau (hTau2N4RE14) induced profound neurodegeneration, supporting a neurotoxic role for phosphorylation. However, when we rendered hTau2N4RE14 aggregation incompetent, by deleting the 306VQIVYK311 motif in the microtubule-binding region, neurotoxicity was abolished. Moreover, a peptide inhibitor targeting this motif efficaciously reduced Tau toxicity in aging Drosophila. ConclusionNeurodegeneration mediated by Tau hyperphosphorylation is gated via at least one aggregation-mediating motif on the protein. This highlights the primacy of blocking Tau aggregation in therapy, perhaps without the need to clear phosphorylated species.

neuroscience↗

bioRxiv2024

A multi-model approach defines function altering MECP2 missense variants identified in individuals with autism spectrum disorder

Pathogenic variants in MECP2 commonly lead to Rett syndrome, where MECP2s function as a DNA cytosine methylation reader is believed critical. MECP2 variants are also catalogued in individuals with autism spectrum disorder (ASD), including nine missense variants which had no known clinical significance at the start of this study. To assess these nine variants as risk alleles for ASD, we developed MECP2 variant functional assays using budding yeast and Drosophila. We calibrated these assays with known pathogenic and benign variants. Our data predict that four ASD variants are loss of function and five are functional. Protein destabilization offers insight into the altered function of some of these variants. Notably, yeast and Drosophila lack DNA methylation, yet all Rett pathogenic and ASD variants located in the methyl DNA binding domain that we analyzed proved to be loss of function, suggesting a clinically-relevant role for non-methyl DNA-binding by MECP2.

neuroscience↗

bioRxiv2024

Individual variation in red deer responsiveness towards human disturbance: A prospect for wildlife viewing in Europes national parks.

Animals adjust behavior to changes in perceived predation risk, even when risk is non-consumptive, as is the case for human recreation. However, individuals within populations can differ greatly in their plasticity towards perceived risk, especially when antipredator responses incur fitness costs via lost foraging opportunities. Therefore, risk-benefit trade-offs are usually made at the individual level. We test whether red deer (Cervus elaphus) inhabiting the Bavarian Forest National Park show individual variation in behavioral plasticity towards human disturbance. We measured human disturbance as the number of recreationists on the closest trail on a given day and used random regression to dissolve movement responses, measured as hourly step-length, of 63 GPS-collared red deer females to fine scale spatio-temporal variation in disturbance. We quantified behavioral state specific between-individual variation along the disturbance gradient. At the population level, red deer responded to recreational disturbance during the middle of the day only, and reduced movement in response to recreation. However, population patterns masked strong between-individual variation in plasticity to recreation activity during the morning, midday, and evening, such that some deer reacted with flight while others responded little. Behavioral responses were mediated by vegetation cover with stronger responses in more open areas. Flight responses are costly due to lost foraging opportunities. A shift in risk-benefit trade-offs when risk is non-lethal, as is the case for recreation in many national parks, may favor more human-tolerant individuals over time. Lay summaryWe assessed the individual response of red deer towards recreational activities in the Bavarian Forest National Park, using GPS-telemetry data and modelled daily numbers of tourists on trails. Red deer varied in their fear of humans, most red deer adjusted movement on days with many park visitors, but some individuals did not respond to human disturbance. Individual variation in movement increased with human disturbance. Foraging-risk trade-offs may promote behavioral variation of red deer and their tolerance of humans.

animal behavior and cognition↗