Biology subjects

Komal, P.

Publications and source records attributed to Komal, P..

3 recordsLinked to original sources

bioRxiv2026

Resilience effect of D3 nutraceutical on NMDA receptor hypofunction theory and dysregulated alpha7 nicotinic acetylcholine receptor function in schizophrenia

Vitamin D3 (VD) deficiency is a global health concern, and its supplementation has been shown to alleviate inflammation and oxidative stress across numerous neurological disorders. However, the beneficial effect of this common nutraceutical in schizophrenia (SCZ) remains inadequately explored. The present study investigated the presupplementation effects of VD on positive and cognitive symptoms in a MK-801induced mouse model of SCZ. MK-801, a non-competitive NMDA receptor antagonist, is a widely used drug that mimics some of the psychotic symptoms associated with SCZ. The repeated administration of a single dose of MK-801 (0.5mg/kg; intraperitoneally) for two weeks produced hyperlocomotion, anxiety- like behavior, and working memory deficits in MK-801-induced SCZ-like mice. These behavioral abnormalities were significantly attenuated in VS5 mice (SCZ mice presupplemented with 500 IU/kg/day of VD). At the molecular level, VD rescued gene expression of major NMDA receptor subunits (NR1, NR2A, NR2B), 7 nicotinic acetylcholine receptors (7nAChRs), and neurotrophin factors (NGF and BDNF). A restoration of PSD-95 protein expression, accompanied by downregulation of calcineurin, was also observed in the prefrontal cortex (PFC) of VS5 mice, suggesting protective effects of VD on synaptic communication and function in SCZ. In vitro studies showed that calcitriol (1 M) treatment of HEK-293 T cells transfected with 7nAChRs potentiated the single-channel current amplitude and demonstrated a direct modulatory effect of this nutraceutical on 7nAChRs expression and function. In silico JASPAR analysis further identified putative Vitamin D response elements (VDREs) within the promoter regions of various target genes, supporting the genomic action of VD. Additionally, VD deficiency was observed in Indian SCZ patients, highlighting its potential clinical relevance. Together with our previous findings (Manjari et al., 2022, 2023), the present study also demonstrates anti-inflammatory, anti-cholinesterase, neurotrophic, and synaptic-enhancing effects of VD, deepening our understanding of the multifaceted neuroprotective effects of the "D3" neurosteroid in neuropsychiatric disorders such as SCZ. HighlightsO_LIVD presupplementation improves the behavioral deficits in MK-801 induced SCZ mice. C_LIO_LINutraceutical intervention normalizes the gene expression of major NMDARs subunits namely, NR1, NR2A, NR2B, in the PFC of SCZ mice. C_LIO_LIVD mediates a restoration in the expression and function of 7nAChRs in SCZ mice. C_LIO_LIVD exhibits neuroprotective, neurotrophic, synaptoprotective, anti-inflammatory and anti-acetylcholinesterase effects, highlighting its therapeutic potential in SCZ. C_LI

neuroscience↗

bioRxiv2026

The CYP27A1 - VDR Feedback Rheostat Controls Mitochondrial Protein Homeostasis and Preserves Hippocampal - Striatal Network Integrity to rescue Cognitive impairment in HD condition

Emerging evidence links vitamin D (VD) deficiency to cognitive and motor dysfunction in Huntingtons disease (HD), yet the underlying mechanism remains unclear. Here, we combine in vitro genetic and 3-nitropropionic acid (3-NP)-induced in vivo models of HD to define the mechanistic basis of VD-mediated neuroprotection. We demonstrate that VD supplementation restores cognitive and motor deficits while improving mitochondrial function and cellular survival. Mechanistically, VD enhances mitochondrial fusion and rescues complex II expression, a key defect in HD pathology. We identify the mitochondrial enzyme CYP27A1 as a critical mediator of this effect, as its expression is reduced in HD models but restored upon VD treatment. Overexpression of CYP27A1 recapitulates the protective effects of VD, confirming its central role in maintaining mitochondrial integrity. Furthermore, VD promotes vitamin D receptor (VDR)-dependent transcriptional activation of CYP27A1 and additional nuclear- and mitochondrial-encoded genes, establishing a regulatory feedback loop that supports mitochondrial biogenesis and function. VD supplementation also improves proteostasis via attenuating endoplasmic reticulum stress. Together, our findings uncover a previously unrecognized VD-CYP27A1 axis that links mitochondrial dysfunction to HD pathology and highlight CYP27A1 as a potential therapeutic target.

neuroscience↗

bioRxiv2025

PEX11β-mediated improvement of mitochondrial dysfunction restores behavioral defect and cellular viability in neuropathological conditions

Peroxisomal biogenesis factor 11 beta (Pex11{beta}) is a key regulator of peroxisome proliferation, functioning in coordination with mitochondrial fission proteins. Recent human proteome co-regulation mapping has revealed a distinctive co-expression pattern between Pex11{beta} and components of the mitochondrial respiratory chain complex at the peroxisome-mitochondria interface. In neurodegenerative disorders, such as Huntingtons disease (HD) and Alzheimers disease (AD), mitochondrial dysfunction is primarily associated with impairments in the respiratory chain complexes, particularly Complex II. However, the role of Pex11{beta} in maintaining mitochondrial homeostasis in these two disease conditions remains largely unexplored. In this study, using both in vitro and in vivo models, we identify Pex11{beta} as a critical modulator of mitochondrial dynamics, influencing the balance between fission and fusion. Through targeted knockdown and overexpression experiments, we demonstrate a direct link between Pex11{beta} level and mitochondrial dysfunction, mediated by transcriptional dysregulation of nuclear-encoded Complex II and mitochondrial fusion genes. Restoration of Pex11{beta} expression, along with Complex II and fusion gene level in striatal brain via a peroxisome proliferator & chemical chaperone, significantly alleviates motor and cognitive deficits in 3-NP-induced HD mouse model indicating better mitochondrial health in striatal brain. Furthermore, in silico analysis and ChIP-qPCR reveal Yin Yang 1 (YY1) is a critical transcription factor governing the co-expression of Pex11{beta} and Complex II genes. This establishes a novel transcriptional axis that orchestrates inter-organellar communication. Collectively, our findings position Pex11{beta} as a pivotal mediator of mitochondrial fission-fusion dynamics, linking mitochondrial morphology and oxidative phosphorylation (OXPHOS) to behavioural outcomes, and offering mechanistic insights relevant to amyloid-associated neurodegenerative diseases.

neuroscience↗