Biology subjects

Yasa, S.

Publications and source records attributed to Yasa, S..

6 recordsLinked to original sources

bioRxiv2024

Large-Scale Computational Modeling of H5 Influenza Variants Against HA1-Neutralizing Antibodies

The United States Department of Agriculture has recently released reports that show samples from 2022-2024 of highly pathogenic avian influenza (H5N1) have been detected in mammals and birds (1). To date, the United States Centers for Disease Control reports that there have been 27 humans infected with H5N1 in 2024 (2). The broader potential impact on human health remains unclear. In this study, we computationally model 1,804 protein complexes consisting of various H5 isolates from 1959 to 2024 against 11 hemagglutinin domain 1 (HA1)-neutralizing antibodies. This study shows a trend of weakening binding affinity of existing antibodies against H5 isolates over time, indicating that the H5N1 virus is evolving immune escape of our medical defenses. We also found that based on the wide variety of host species and geographic locations in which H5N1 was observed to have been transmitted from birds to mammals, there is not a single central reservoir host species or location associated with H5N1s spread. These results indicate that the virus has potential to move from epidemic to pandemic status in the near future. This study illustrates the value of high-performance computing to rapidly model protein-protein interactions and viral genomic sequence data at-scale for functional insights into medical preparedness. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSPrevious studies have shown cases of avian influenza transmissions to mammals that are increasing in frequency, which is of concern to human health. Since 1997, nearly a thousand H5N1 cases have been reported in humans with a 52% fatality rate. Previous analyses have indicated specific mutations on the hemagglutinin protein that allow for this "host jumping" between birds and mammals (3). There are also existing evidence of recent viral strains with reduced neutralization to sera (4). Added value of this studyThis study provides a comprehensive look at the mutational space of hemagglutinin of H5N1 influenza and presents computational predictions of the binding between various HA1-neutralizing antibodies derived from infected vaccinated patients and humanized mice and 1,804 representative H5 HA1 proteins. These analyses show a weakening trend of existing antibodies. We also confirm that the mutations found in other studies that enable zoonosis also affect binding affinities of the antibodies tested. Furthermore, through phylogenetic analyses, we quantify the avian-to-mammalian transmissions from 1959 to 2024 and show a persistent circulation of isolates between North America and Europe. Taken together, the continuous transmission of H5N1 from birds to mammals and the increase in immuno-evasive HA strains in mammals sampled over time suggest that antigenic drift is a source of spillover risk. Implications of all the available evidenceOur findings indicate that the worsening in antibody binding, along with the increase in of avian-to-mammalian H5N1 influenza transmissions are risks to public health. Through the findings of previous studies along with the predictions reported in this study, we can now monitor specific mutations of interest, quantified by their potential impact on antibody evasion, and inform public health monitoring of circulating isolates in 2024 and beyond. In addition, these findings may help to guide future vaccine and therapeutic development in the fight against H5N1 influenza infections in humans.

bioinformatics↗

bioRxiv2024

Loss of CLN3 in microglia leads to impaired lipid metabolism and myelin turnover

BackgroundMicroglia are the primary brain cell type regulating neuroinflammation and they are important for healthy aging. Genes regulating microglial function are associated with an increased risk of neurodegenerative disease. Loss-of-function mutations in CLN3, which encodes an endolysosomal membrane protein, lead to the most common childhood-onset form of neurodegeneration, featuring early-stage neuroinflammation that long precedes neuronal cell loss. How loss of CLN3 function leads to this early neuroinflammation is not yet understood. MethodsHere, we have comprehensively studied microglia from Cln3{Delta}ex7/8 mice, a genetically accurate CLN3 disease model. Microglia were isolated from young and old Cln3{Delta}ex7/8 mice for downstream molecular and functional studies. ResultsWe show that loss of CLN3 function in microglia leads to classic age-dependent CLN3-disease lysosomal storage as well as an altered morphology of the lysosome, mitochonodria and Golgi compartments. Consistent with these morphological alterations, we also discovered pathological proteomic signatures implicating defects in lysosomal function and lipid metabolism processes at an early disease stage. CLN3-deficient microglia were unable to efficiently turnover myelin and metabolize its associated lipids, showing severe defects in lipid droplet formation and significant accumulation of cholesterol, phenotypes that were corrected by treatment with autophagy inducers and cholesterol lowering drugs. Finally, we observed reduced myelination in aging homozygous Cln3{Delta}ex7/8 mice suggesting altered myelin turnover by microglia impacts myelination in the CLN3-deficient brain. ConclusionOur results implicate a cell autonomous defect in CLN3-deficient microglia that impacts the ability of these cells to support neuronal cell health. These results strongly suggest microglial targeted therapies should be considered for CLN3 disease.

neuroscience↗

bioRxiv2023

Positing changes in neutralizing antibody activity for SARS-CoV-2 XBB.1.5 using in silico protein modeling

The SARS-CoV-2 variant XBB.1.5 is of concern as it has high transmissibility. XBB.1.5 currently accounts for upwards of 30% of new infections in the United States. One year after our group published the predicted structure of the Omicron (B.1.1.529) variants receptor binding domain (RBD) and antibody binding affinity, we return to investigate the new mutations seen in XBB.1.5 which is a descendant of Omicron. Using in silico ico modeling approaches against newer neutralizing antibodies that are shown effective against B.1.1.529, we predict the immune consequences of XBB.1.5s mutations and show that there is no statistically significant difference in overall antibody evasion when comparing to the B.1.1.529 and other related variants (e.g., BJ.1 and BM.1.1.1). However, noticeable changes in antibody binding affinity were seen due to specific amino acid changes of interest in the newer variants.

biochemistry↗

bioRxiv2022

The Batten disease protein CLN3 is important for stress granules dynamics and translational activity.

The assembly of membrane-less organelles such as stress granules (SGs) is emerging as central in helping cells rapidly respond and adapt to stress. Following stress sensing, the resulting global translational shutoff leads to the condensation of stalled mRNAs and proteins into SGs. By reorganising cytoplasmic contents, SGs can modulate RNA translation, biochemical reactions and signalling cascades to promote survival until the stress is resolved. While mechanisms for SG disassembly are not widely understood, the resolution of SGs is important for maintaining cell viability and protein homeostasis. Mutations that lead to persistent of aberrant SGs are increasingly associated with neuropathology and a hallmark of several neurodegenerative diseases. Mutations in CLN3 are causative of juvenile neuronal ceroid lipofuscinosis (JNCL), a rare neurodegenerative disease affecting children. CLN3 encodes a transmembrane lysosomal protein implicated in autophagy, endosomal trafficking, metabolism, and response to oxidative stress. Using a HeLa KO model, we now show that CLN3KO is associated with an altered metabolic profile, reduced global translation, and altered stress signalling. We further demonstrate that loss of CLN3 results in perturbations in SG dynamics, resulting in assembly and disassembly defects, and altered expression of the key SG nucleating factor G3BP1. With a growing interest in SG-modulating drugs for the treatment of neurodegenerative diseases, novel insights into the molecular basis of CLN3 Batten disease may reveal avenues for disease-modifying treatments for this debilitating childhood disease.

molecular biology↗

bioRxiv2020

CLN5 and CLN3 function as a complex to regulate endolysosome function

CLN5 is a soluble endolysosomal protein whose function is poorly understood. Mutations in this protein cause a rare neurodegenerative disease, Neuronal Ceroid Lipofuscinosis. We previously found that depletion of CLN5 leads to dysfunctional retromer, resulting in the degradation of the lysosomal sorting receptor, sortilin. However, how a soluble lysosomal protein can modulate the function of a cytosolic protein, retromer, is not known. In this work, we show that deletion of CLN5 not only results in retromer dysfunction, but also in impaired endolysosome fusion events. This results in delayed degradation of endocytic proteins and in defective autophagy. CLN5 modulates these various pathways by regulating downstream interactions between CLN3, an endolysosomal integral membrane protein whose mutations also result in Neuronal Ceroid Lipofuscinosis, Rab7A, and a subset of Rab7A effectors. Our data supports a model where CLN3 and CLN5 function as an endolysosome complex regulating various functions. Summary StatementWe have previously demonstrated that CLN3 is required for efficient endosome-to-trans Golgi Network (TGN) trafficking of sortilin by regulating retromer function. In this work, we show that CLN5, which interacts with CLN3, regulates retromer function by modulating key interactions between CLN3, Rab7A, retromer, and sortilin. Therefore, CLN3 and CLN5 serve as endosomal switch regulating the itinerary of the lysosomal sorting receptors.

cell biology↗

bioRxiv2019

CLN3 regulates endosomal function by modulating Rab7A activity

Mutations in CLN3 are a cause of juvenile NCL (JNCL), also known as Batten Disease. Clinical manifestations includes cognitive regression, progressive loss of vision and motor function, epileptic seizures, and a significantly reduced lifespan. CLN3 localizes to endosomes and lysosomes, and has been implicated in intracellular trafficking and autophagy. However, the precise molecular function of CLN3 remains to be elucidated. We show that CLN3 interacts with Rab7A, a small GTPase that regulates several functions at late endosomes. We found that CLN3 is required for the efficient endosome-to-TGN trafficking of the lysosomal sorting receptors by regulating the Rab7A/retromer interaction. In cells lacking CLN3 or expressing CLN3 harbouring a disease-causing mutation, the lysosomal sorting receptors were degraded. We also demonstrated that CLN3 is required for the Rab7A/PLEKHM1 interaction, which is required for autophagosome/lysosome fusion. Overall, our data provides a molecular explanation behind phenotypes observed in JNCL.

cell biology↗