Dr. Shekhar has recently joined Centre of BioMedical Research, SGPGIMS, Campus, Lucknow, where his research focuses on understanding the role of biomolecular condensates in regulation of neuronal stress responses and neurodegenerative diseases.  As postdoc, Dr. Shekhar has investigated molecular mechanisms regulating proteostasis in the nervous system. He discovered a functionally conserved secreted pseudokinase, Allnighter (Aln), to be a critical part of a feedback loop regulating structural plasticity in the Drosophila visual system. During long-term adaptation in the visual system, Aln is critical for proteostasis regulation including unfolded protein response in endoplasmic reticulum (UPRER) and autophagy. This is the first example of a pseudokinase being secreted and affecting adaptation in another cell type (Shekhar et al., Nature Communications 2023).

Subsequently, he discovered a new mechanism for stress-driven proteostasis regulation. He observed that sensory disabilities trigger a cell non-autonomous integrated stress response (ISR). However, unlike the canonical ISR (where transcription factors (TFs) enter nuclei to restore homeostasis or to induce apoptosis under chronic conditions), the ISR-induced TFs ATF4 and XRP1 form cytosolic condensates matching multiple aspects of stress granules (SGs). Sequestration of these TFs in SGs mitigates ISR-activated transcriptional rewiring and protects cells from ATF4/XRP1-induced death by dampening TF function. He termed this novel mechanism of proteostasis regulation Chronic Stress Protective Response (CSPR) (Shekhar et al., Nature Communications 2025). These results highlight a novel activity-dependent, cell non-autonomous proteostasis regulation in neurons and reveal an in-vivo function of neuronal SGs.

Furthermore, he used an acute stress model in-vivo (as published in Shekhar et al., Nature Communications 2023) to investigate the role of biomolecular condensates in neuronal structural plasticity. His research revealed that the p62 adaptor protein undergoes phase separation to form condensates distinct from the ATF4/XRP1 condensates induced by CSPR. Importantly, the formation of these condensates does not depend on a block in autophagy but requires eIF2α-S50 phosphorylation and UFMylation - two critical processes for maintaining cellular homeostasis (Shekhar et al., in preparation).

Together his research underscores the significant role of biomolecular condensates in neurons, representing a pioneering effort to elucidate their in-vivo function and provide tools to investigate their role in neurodegeneration.

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  Neurons are set apart from other cell types by distinct features. These include post-mitotic status requiring their extended survival, intricate morphology defining their participation in complex neural circuits and dynamic regulation of individual synapses. These distinct features necessitate specialized mechanisms to respond to stress and restore homeostasis to promote neuronal survival. I used Drosophila photoreceptors as my model and ambient constant light paradigm (LL) as stressor to understand the mechanisms regulating neuronal structural plasticity. I discovered that, under LL photoreceptor neurons reduce their size by almost one-third. This adaptive change requires multiple stress response pathways and is reversible upon removal of the stressor.

  

   

  

  Sensory disabilities have been identified as significant risk factors for dementia but underlying molecular mechanisms are unknown. A common aspect of different neurodegenerative disorders, including dementia, is dysregulated protein homeostasis or proteostasis.  I investigated the impact of failure of sensory output in different models of drosophila and mouse on brain-wide proteostasis and found that sensory disabilities disrupt proteostasis in both Drosophila and mouse models.

  

   

  

  During my doctoral research I found that the level of Tau, p-Tau181, and 5-Lipoxygenase in serum of Alzheimer’s and MCI patients is elevated. This was the first report for a blood-based biomarker in the field. I used Surface Plasmon Resonance technology to measure serum levels of these proteins. Concretely, I designed and synthesized phospho-peptide epitope of p-Tau181 to quantify the serum level. As blood-based markers have several advantages over the invasive CSF or expensive MRI and PET-Scans, my research established a foundation for less invasive and highly cost-effective circulatory biomarkers for Alzheimer’s disease.

1.     Shekhar S, Tracy C, Lidsky PV, Andino R, Wert KJ, Krämer H. Sensory quiescence induces a cell-non-autonomous integrated stress response curbed by condensate formation of the ATF4 and XRP1 effectors. Nature Communications.2025;16:252.
[Spotlight: Besse F. Trends Neurosci. 2025. doi:10.1016/j.tins.2025.02.007.]

2.     Shekhar S^#, Moehlman AT, Park B, Ewnetu M, Tracy C, Titos I, et al. Allnighter pseudokinase-mediated feedback links proteostasis and sleep in Drosophila. Nature Communications. 2023;14:2932. (^# Co-corresponding author)

3.     Kumari S, Singh A, Singh AK, Yadav Y, Bajpai S, Upadhyay AK, et al. Circulatory GSK-3β: blood-based biomarker and therapeutic target for Alzheimer’s disease. J Alzheimers Dis. 2022;85(1):249–60.

4.     Shekhar S, Tripathi M, Dey AB, Dey S. Exploring the serum level of RE1 silencing transcription factor in Alzheimer’s disease. Ann Natl Acad Med Sci (India). 2021;00:1–5.

5.     Anwar M, Mallick SR, Paliwal D, Sekhar S, Panda SK, Dey S, et al. Impact of physical activity on mitochondrial enzymes, muscle stem cell and antioxidant protein Sestrins in sarcopenic mice. Exp Gerontol. 2021;150:111358.

6.     Shekhar S, Dey S. Induction of p73, Δ133p53, Δ160p53, pAKT lead to neuroprotection via DNA repair by 5-LOX inhibition. Mol Biol Rep. 2020;47:269–74.

7.     Pradhan R, Yadav SK, Prem NN, Bhagel V, Pathak M, Shekhar S, et al. Serum FOXO3A: a ray of hope for early diagnosis of Alzheimer’s disease. Mech Ageing Dev. 2020;190:111290.

8.     Singh AP, Nigam L, Yadav Y, Shekhar S, Subbarao N, Dey S. Design and in vitro analysis of SIRT2 inhibitor targeting Parkinson’s disease. Mol Divers. 2020; 25:2261-2270.

9.     Sahu V, Nigam L, Agnihotri V, Gupta A, Shekhar S, Subbarao N, et al. Diagnostic significance of p38 isoforms (p38α, p38β, p38γ, p38δ) in head and neck squamous cell carcinoma: comparative serum level evaluation and design of novel peptide inhibitor. Cancer Res Treat. 2019;51(1):313–25.

10.  Shekhar S, Yadav Y, Singh AP, Pradhan R, Desai GR, Dey AB, et al. Neuroprotection by ethanolic extract of Syzygium aromaticum in Alzheimer’s disease-like pathology via maintaining oxidative balance through SIRT1 pathway. Exp Gerontol. 2018;110:277–83.

11.  Shekhar S, Yadav SK, Rai N, Kumar R, Yadav Y, Tripathi M, et al. 5-LOX in Alzheimer’s disease: potential serum marker and in vitro evidences for rescue of neurotoxicity by its inhibitor YWCS. Mol Neurobiol. 2018;55(4):2754–62.

12.  Pradhan R, Kumar R, Shekhar S, Rai N, Ambashtha A, Banerjee J, et al. Longevity and healthy ageing genes FOXO3A and SIRT3: serum protein markers and new roadmap to burst oxidative stress by Withania somnifera. Exp Gerontol. 2017;95:9–15.

13.  Singh K, Shekhar S, Yadav Y, Xess I, Dey S. DS6: anticandidal, antibiofilm peptide against Candida tropicalis and exhibits synergy with commercial drug. J Pept Sci. 2017;23(3):228–35.

14.  Shekhar S, Kumar R, Rai N, Kumar V, Singh K, Upadhyay AD, et al. Estimation of Tau and phosphorylated Tau 181 in serum of Alzheimer’s disease and mild cognitive impairment patients. PLoS One. 2016;11(7):e0159099.

15.  Rai N, Kumar R, Desai GR, Venugopalan G, Shekhar S, Chatterjee P, et al. Relative alterations in blood-based levels of Sestrin in Alzheimer’s disease and mild cognitive impairment patients. J Alzheimers Dis. 2016;54(3):1147–55.

16.  Kumar R, Singh AK, Kumar M, Shekhar S, Rai N, Kaur P, et al. Serum 5-LOX: a progressive protein marker for breast cancer and new approach for therapeutic target. Carcinogenesis. 2016;37(9):912–17.

17.  Singh K, Kumar S, Shekhar S, Dhawan B, Dey S. Synthesis and biological evaluation of novel peptide BF2 as an antibacterial agent against clinical isolates of vancomycin-resistant enterococci. J Med Chem. 2014;21:8880–5.

📚 Book Chapters

1.     Dey S, Rai N, Shekhar S, Singh AP, Agnihotri V. Molecular marker and therapeutic regimen for neurodegenerative diseases. In: Rath P, editor. Models, Molecules and Mechanisms in Biogerontology. Singapore: Springer; 2019.

2.     Nandi N, Shekhar S. Role of medical biotechnology research in the field of neurodegenerative disease treatment. In: Talukder P, editor. Exploring Medical Biotechnology: in vivo, in vitro, in silico – Biotechnology from Labs to Clinics. Abingdon: Routledge; 2023.