Biology subjects

Raj, V.

Publications and source records attributed to Raj, V..

3 recordsLinked to original sources

bioRxiv2024

Dopamine controls the Sensitivity to Manganese induced Dopaminergic neurotoxicity in Caenorhabditis elegans

Manganism, a disease with characteristic degeneration of dopamine neurons, has distinct aetiology and clinical manifestations, striking similarities with Parkinsons Disease (PD). Environmental exposure to manganese (Mn) is one of the risk factors for the occurrence of PD. The definitive role of dopamine (DA) in Mn mediated neurodegeneration, and its developmental impact has not been well studied. To understand the pathways involved in Mn-induced neurotoxicity, we used C. elegans as the model system. Our results showed that adult worms treated with 50 and 100 mM MnCl2 significantly increased DA neurodegeneration. L1 larvae spared without neurodegeneration when treated with MnCl2 alone showed a significant increase in neurodegeneration (>50%) when MnCl2 exposure was given after DA pretreatment. However, both adult and larval exposure to MnCl2 demonstrated significant toxicity by reducing the survival rate. In adult worms, 100 mM MnCl2 treatment after DA pretreatment further elevated the percentage of neurodegeneration. The Mn or DA alone exposed adult worms showed recovery of neuronal dopamine function within 24 hours, although exogenous DA and Mn treated worms showed prolonged behavioural defects. Cat-2 mutants, without DA, were resistant to Mn mediated neurodegeneration. In contrast, Cat-2 overexpressing strain displayed severe neurodegeneration at lower concentrations of MnCl2 (50 mM). Our results on biochemical, behavioural and genetic assays proved endogenous/exogenous DA level controls the sensitivity to Mn induced dopaminergic neurotoxicity.

pharmacology and toxicology↗

bioRxiv2024

The abundance change of age-regulated secreted proteins affects lifespan of C. elegans

Proteome integrity is vital for survival and failure to maintain it results in uncontrolled protein abundances, misfolding and aggregation which cause proteotoxicity. In multicellular organisms, proteotoxic stress is communicated among tissues to maintain proteome integrity for organismal stress resistance and survival. However, nature of these signalling molecules and their regulation in extracellular space is largely unknown. Secreted proteins are induced in response to various stresses and aging, indicating their roles in the inter tissue communication. To study fates of age-regulated proteins with potential localization to extracellular, we analysed publicly available age-related proteome data of C. elegans. We found that abundance of proteins with signal peptides (SP) increases with age and result in their aggregation. Intriguingly, these changes are differentially regulated in the lifespan mutants. A subset of these SP proteins is also found in the cargo of extracellular vesicles. Many of these proteins are novel and functionally uncharacterized. Reducing levels of a few extracellular proteins result in increasing lifespan. This suggest that uncontrolled levels of extracellular proteins might disturb proteostasis and limit the lifespan. Overall, our findings suggest that the age induced secreted proteins might be the potential candidates to be considered as biomarkers or for mitigating age-related pathological conditions.

biochemistry↗

bioRxiv2022

HAPNEST: efficient, large-scale generation and evaluation of synthetic datasets for genotypes and phenotypes

Existing methods for simulating synthetic genotype and phenotype datasets have limited scalability, constraining their usability for large-scale analyses. Moreover, a systematic approach for evaluating synthetic data quality and a benchmark synthetic dataset for developing and evaluating methods for polygenic risk scores are lacking. We present HAPNEST, a novel approach for efficiently generating diverse individual-level genotypic and phenotypic data. In comparison to alternative methods, HAPNEST shows faster computational speed and a lower degree of relatedness with reference panels, while generating datasets that preserve key statistical properties of real data. These desirable synthetic data properties enabled us to generate 6.8 million common variants and nine phenotypes with varying degrees of heritability and polygenicity across 1 million individuals. We demonstrate how HAPNEST can facilitate biobank-scale analyses through the comparison of seven methods to generate polygenic risk scoring across multiple ancestry groups and different genetic architectures.

bioinformatics↗