Biology subjects

Bisht, K. S.

Publications and source records attributed to Bisht, K. S..

4 recordsLinked to original sources

bioRxiv2026

Bisphenol-A mediated ubiquitinome alteration triggers PPAR-alpha ubiquitination, affecting trophoblast cell migration

Pregnant women are frequently exposed to various endocrine-disrupting chemicals (EDCs), such as bisphenol A (BPA), causing harm to both the developing placenta and fetus. BPA can promote placental dysfunction by altering key cellular processes such as differentiation, invasion, and migration in trophoblast cells. These cellular processes are also tightly managed by the ubiquitin proteasomal system via maintenance of the ubiquitinated protein pool. However, the BPA-mediated dysregulation of this ubiquitin proteasomal homeostasis is poorly understood. Therefore, we identified 19 deubiquitinases (DUBs) and a dynamic ubiquitinome profile of extravillous trophoblast cells (HTR8/SVneo), which reduced trophoblast cell migration post-BPA exposure. Further investigation using an integrated substrate-ligase-deubiquitinase network shows that BPA binding to PPAR-alpha or indirect regulation of its E3 Ligase MuRF1 and DUB USP5 via BPA resulted in hyper-ubiquitination of PPAR-alpha, triggering its nuclear localization. In the nucleus, the ubiquitinated PPAR-alpha can deregulate its migration-associated target gene expression, causing a reduction in the migration of HTR8/SVneo cells. This physiological alteration of extravillous trophoblast cells (EVTs) through BPA can disrupt placental homeostasis. Hence, we assumed that BPA-induced cellular alteration in EVTs can promote placental defects, which might contribute to adverse pregnancy outcomes.

biochemistry↗

bioRxiv2026

Ferroptosis links α-synuclein pathology across brain and skeletal muscle in Parkinsons disease

Parkinsons disease (PD) is increasingly recognized as a multisystem disorder, yet the mechanisms linking neurodegeneration with muscle dysfunction remain largely unknown. In this study, using an A53T -synuclein (Syn) transgenic mouse model, we demonstrate coordinated pathological changes across the brain-muscle organs characterized by systemic inflammation, iron accumulation, oxidative stress, and ferroptosis-associated lipid peroxidation. Our quantitative proteomics data revealed dysregulated iron metabolism and ferroptosis in the brain and skeletal muscle. Biochemical validation confirmed increased expression of Transferrin receptor 1 (TFRC), elevated lipid peroxidation, and suppression of antioxidant defenses, including SLC7A11 and GPX4, indicating enhanced ferroptotic susceptibility. Cell-surface proteomics and biophysical assays further revealed that pathological Syn directly interacts with TFRC, promoting iron accumulation and ferroptosis-associated oxidative damage in neuronal and muscle cells. Together, our findings identify ferroptosis as a shared pathological mechanism across the brain and muscle, mediated by the Syn-TFRC interaction, thus linking neurodegeneration and peripheral muscle pathology in PD.

neuroscience↗

bioRxiv2025

Synapse-related protein alterations and estradiol deficiency associate with early Parkinsonism in female A53T-α-synuclein transgenic mice fed on a high-fat diet

Substantial evidence highlights the detrimental impact of a fat-rich diet on cognitive and emotional behaviour. Epidemiological studies have linked the consumption of saturated fat with an increased risk of Parkinsons disease (PD), whereas a low-fat or ketogenic diet is reported to improve both motor and non-motor symptoms. Several animal model studies further support these associations. However, the impact of a high-fat diet (HFD) on sex-specific behavioural alterations and the underlying molecular mechanism in PD remains poorly studied. In the present study, we investigated the impact of HFD on PD progression in a sex-specific manner using the A53T transgenic mouse model of PD. Behavioural and pathophysiological analyses revealed a faster onset and progression of PD-like phenotype in female mice exposed to HFD compared with the male mice. Proteomics profiling of brain tissues demonstrated positive enrichment of immune system-related pathways in males, while females exhibited considerable downregulation of synapse-associated pathways under HFD conditions. The reduced estradiol level was identified as a potential factor contributing to synaptic dysfunction and the subsequent early onset of PD in female mice. These findings provide novel insights into the sex-specific consequences of HFD on PD pathogenesis and highlight the role of estrogen-linked synaptic vulnerability in mediating diet-induced PD onset.

neuroscience↗

bioRxiv2022

Glycation renders alpha-synuclein oligomeric strain and modulates microglia activation

-Synuclein is known to involve in the pathogenesis of Parkinsons diseases (PD) and related disorders. However, it is unclear how its aggregation causes neuronal degeneration and neuroinflammation. Due to intrinsic disorder nature, -synuclein produces a large number of structural ensembles and diverse aggregation intermediates. The post-translational modifications add a new layer of complexity to the aggregation mechanism. Recently, it has been demonstrated that glycation of -synuclein restricts into oligomeric intermediates and causes neuronal toxicity. However, the understanding of aggregation mechanism, dopaminergic neuronal death, and neuroinflammation by the glycated -synuclein is yet to be elucidated. The present study aims to address how glycated synuclein differs in oligomerization and neuroinflammation. The glycation of -synuclein perturbs the aggregation kinetics and prevents the fibrilization through the alteration of surface charges of N-terminal domain residues which prevents membrane binding and seed amplification mechanism. Mass spectrometry-based proteomics analysis of BV2 cells treated with glycated oligomers provides evidence of alteration of endocytic mechanism, mitochondrial dysfunction, and inflammatory cascade. Here, we show that -synuclein oligomers strongly bind to TLR2 and activate the TLR2 mediated signaling. However, glycated -synuclein oligomers impair the TLR2 binding and compromise TLR2 signaling. Interestingly, we also find that the glycated -synuclein oligomers favor NLRP3 inflammasome mediated neuroinflammation compared to non- glycated -synuclein oligomers. In conclusion, our findings suggest that microglia response towards -synuclein is conformation-specific and glycated oligomers can contribute to neurodegeneration differently.

neuroscience↗