Biology subjects

Miller, Y.

Publications and source records attributed to Miller, Y..

3 recordsLinked to original sources

bioRxiv2026

Site-specific phosphorylation of Ser352 drives aggregation of Tau R4 under acidosis conditions

In Alzheimers disease, neurons undergo acidosis as their pH drops from [~]7.1 to [~]6.5. Here we elucidate the molecular mechanism of specific Tau aggregation only at this lower pH. We show that a specific phosphorylation event in the Tau R4 domain is coupled to this pH drop to drive a defined phase transition from condensates to fibrils. Using a combination of experimental and computational studies, our results demonstrate that site-specific phosphorylation of Ser352 is the molecular switch that induces aggregation of Tau only at the more acidic, disease-related pH. We designed and synthesized a phosphopeptide library covering all phosphorylation patterns of the Tau-R4 domain and tested its response to controlled acidification using an array of complementary biophysical methods. This revealed that only a single phosphorylation of Ser352 led to acid-driven aggregation of Tau-R4. At neutral pH, Tau-R4 with a phosphorylation on Ser352 formed liquid condensates. These condensates converted irreversibly into amyloid filaments as the pH gradually decreased towards the level associated with pathological acidosis. Using a combination of 3{superscript 1}P-and 1H - NMR, MD simulations and microscopy studies, we show that the mechanism by which the phosphorylation of Ser352 Tau R4 exerts its effects is based on the unique position of this residue within the protein structure. pSer352 is located at the inside of the tip of a {beta}-hairpin, pointing into the hydrophobic core of the amyloid fold. This buried position increases its effective pK{square}, resulting in compacting of the hairpin following pSer352 protonation upon acidification. This shortens the inter-sheet distance at this position and tightens the filament. We conclude that this single protonation event of the pSer352 phosphate is responsible for the macroscopic phase transition from condensates to aggregates. Our results provide the molecular explanation for the specific aggregation of Tau under the pathologically relevant acidic pH, which is substantially different from its behavior at neutral pH.

biochemistry↗

bioRxiv2024

Factors affecting the individual probability of infection with a prevalent pathogen (Mycoplasma) and the effect on Griffon vultures' movement behavior

Mycoplasmas are known as commensals and pathogenic bacteria of various raptor species causing clinical or subclinical infections. However, little is known about the prevalence of mycoplasma in captive and wild raptors and its significance to their health. In Israel, the Griffon vulture (Gyps fulvus; hereafter Griffons) is considered critically endangered, and its intensive management program includes population monitoring and restocking (captive-born or imported rehabilitated wild Spanish Griffons). Here we survey the prevalence of Mycoplasma species in both the wild and captive populations. During 2019-2020, we collected 244 tracheal swab samples from 167 unique individuals. We used PCR analysis to identify Mycoplasma species. First, we identified nine spp., including species not yet described in Israel or for Griffon vultures. Second, imported Griffons showed a higher prevalence and a different diversity of species in comparison to the local ones, suggesting that at least one Mycoplasma species (Sp 18b) was introduced into the native population. Third, juvenile Griffons had a higher prevalence, different species composition, and stronger reduction in movement compared to adults, confirming the susceptibility of this group to mycoplasma infections. GPS-tracking of 60 free-ranging individuals showed that even in the absence of apparent clinical signs, Griffons infected with mycoplasma, and especially sub-adults flew less (shorter distances and periods). These findings underscore the importance of considering potential pathogen introductions in population reinforcement and reintroduction initiatives, providing valuable insights for similar conservation programs globally. Further, they demonstrate the potential of long-term tracking for detecting subclinical effects that are unnoticeable in clinical examination.

ecology↗

bioRxiv2024

Extreme temperatures impede the release success of captive-bred avian scavengers

Conservation translocations (reinforcements and reintroductions) are central for managing various endangered species, yet, their implementation is logistically and financially challenging. Because many translocations fail due to the mortality of released individuals, identifying and preventing these factors is crucial. Here we examine risk factors affecting the post-release survival of the Griffon vulture (Gyps fulvus). The Israeli population is facing extinction, and the recovery efforts by the local Nature and Parks Authority include supplemental releases of individuals from captive-breeding or rehabilitated birds (mostly imported from Spain). We use GPS tracking and thermometers to compare movement, behavior, and weather conditions experienced by released and wild-born individuals active in the same area and time. Our results show that the Judean Desert release site had a significantly lower survival rate than other release sites included in the program. After excluding several possible factors (e.g. known pathogens) with pathological examinations, we found that released individuals at this area were exposed to higher temperatures preceding their death (compared to wild-born griffons nearby), suggesting heat stress as the cause of death. Arguably, they failed to avoid the harsh environmental conditions, resulting in overheating due to their inexperience and undeveloped flight ability, as reflected by their lower probabilities of flying and shorter travel distances per day compared to wild-born vultures. These findings have led to adjustments of the local release protocol, (namely winter releases) resulting in a significant improvement in the early survival of translocated Griffons in the Judean Desert. Accounting for the harmful effects of extreme weather conditions is particularly important in a world facing climate change. More broadly, this sequence of scientific investigation with data integration from ecological, clinical, and biotelemetry sources, leading to improvement in translocation success demonstrates how conservation practices can be optimized by supporting studies to ensure the survival of endangered species in the wild.

ecology↗