Dissertation Defense: The effects of complex I deficiency on neurogenesis and white matter development in a mouse model of Leigh Syndrome (LS)
Dissertation Defense: The effects of complex I deficiency on neurogenesis and white matter development in a mouse model of Leigh Syndrome (LS)
Sahitya Ranjan Biswas
Graduate Student, Translational Biology, Medicine, and Health
Graduate Research Assistant, Pickrell Lab, School of Neuroscience
October 9, 2025, at 1 p.m.
Life Sciences 1, Room 101
More About the Candidate and Project
Education
Virginia Tech, Translational Biology, Medicine, and Health, Ph.D. Candidate
University of Dhaka, M.S., Microbiology
University of Dhaka, B.S., Microbiology
Training
Graduate Research Assistant, Pickrell Lab, School of Neuroscience
Mentors
Alicia M. Pickrell, Ph.D., Associate Professor, Director of Graduate Studies, School of Neuroscience
Committee Members
- Paul Morton, Ph.D., Assistant Professor, Department of Biomedical Sciences and Pathobiology, VA-MD College of Veterinary Medicine
- Shannon Farris, Ph.D., Assistant Professor, Fralin Biomedical Research Institute at VTC
- Joshua Drake, Ph.D., Assistatn Professor, Department of Human Nutrition, Foods, and Exercise
Publications
Biswas, S. R., Tomsick, P. L., Kelly, C., Lester, B. A., Milner, J. P., Henry, S. N., Soto, Y., Brindley, S., DeFoor, N., Morton, P. D., & Pickrell, A. M. (2025). Impaired Complex I dysregulates neural/glial precursors and corpus callosum development revealing postnatal defects in Leigh Syndrome mice. bioRxiv : the preprint server for biology, 2025.05.16.654318. https://doi.org/10.1101/2025.05.16.654318 *In revision
Paul, S., Brindley, S., Biswas, S. R., DeFoor, N., Zavar, L., Wright, G., Soto, Y., and Pickrell, A. M. (2025). Disrupted autophagy overactivates TBK1 and results in mitotic defects promoting micronucleation. *In revision
Paul S*., Biswas S. R*., Milner J. P., Tomsick P., & Pickrell, A. M. (2025). Adaptor-Mediated Trafficking of Tank Binding Kinase 1 During Diverse Cellular Processes. Traffic, 26: e70000. https://doi.org/10.1111/tra.70000 *co-first authorship
Paul, S., Sarraf, S. A., Nam, K. H., Zavar, L., DeFoor, N., Biswas, S. R., Fritsch, L. E., Yaron, T. M., Johnson, J. L., Huntsman, E. M., Cantley, L. C., Ordureau, A., & Pickrell, A. M. (2024). NAK-associated protein 1/NAP1 activates TBK1 to ensure accurate mitosis and cytokinesis. The Journal of cell biology, 223(2), e202303082. https://doi.org/10.1083/jcb.202303082
Jubyda, F. T., Nahar, K. S., Barman, I., Johura, F. T., Islam, M. T., Sultana, M., Ullah, W., Tasnim, J., Biswas, S. R., Monir, M. M., George, C. M., Camilli, A., Ahmed, N., Ross, A. G., Clemens, J. D., & Alam, M. (2023). Vibrio cholerae O1 associated with recent endemic cholera shows temporal changes in serotype, genotype, and drug-resistance patterns in Bangladesh. Gut pathogens, 15(1), 17. https://doi.org/10.1186/s13099-023-00537-0
Biswas, S. R.*, Johura, F. T.*, Rashed, S. M., Islam, M. T., Islam, S., Sultana, M., Watanabe, H., Huq, A., Thomson, N. R., Colwell, R. R., & Alam, M. (2022). Vibrio cholerae O1 El Tor strains linked to global cholera show region-specific patterns by pulsed-field gel electrophoresis. Infection, Genetics and Evolution, 105, 105363. Advance online publication. https://doi.org/10.1016/j.meegid.2022.105363 *co-first authorship
Johura, F. T., Tasnim, J., Barman, I., Biswas, S. R., Jubyda, F. T., Sultana, M., George, C. M., Camilli, A., Seed, K. D., Ahmed, N., & Alam, M. (2020). Colistin-resistant Escherichia coli carrying mcr-1 in food, water, hand rinse, and healthy human gut in Bangladesh. Gut Pathogens, 12, 5. https://doi.org/10.1186/s13099-020-0345-2
Posters
Sahitya Ranjan Biswas, Samantha Brindley, Nicole DeFoor, Sara N. Henry, Yairis Soto, Colin Kelly, Alicia M. Pickrell. Postnatal neurogenesis is disrupted in the SVZ of Ndufs4 knockout mouse model of Leigh syndrome. Mitochondrial medicine’24, United Mitochondrial Disease Foundation, June, 2024. Cleveland, OH.
Sahitya Ranjan Biswas, Samantha Brindley, Nicole DeFoor, Sara N. Henry, Yairis Soto, Colin Kelly, Alicia M. Pickrell. Effects of complex I deficiency and PINK1/ Parkin mediated mitophagy on neurogenesis of the subventricular zone in Ndufs4 KO mouse model of Leigh syndrome. Winter conference on Brain Research, January, 2024. Breckenridge, CO.
Talks
Sahitya Ranjan Biswas, Porter Tomsick, Samantha Brindley, Nicole DeFoor, Sara N. Henry, Yairis Soto, Colin Kelly, Alicia M. Pickrell. Complex I deficiency disrupts the SVZ neurogenic niche in the Ndufs4 knockout mouse model of Leigh syndrome. EMBO workshop in energy balance in metabolic diseases’25, February, 2025. Malaga, Spain.
About this Dissertation
Leigh syndrome (LS) is one of the most common inherited pediatric mitochondrial disorders, typically presenting in early childhood with psychomotor regression and progressive neurological decline. Current understanding suggests that pathogenic variants affecting mitochondrial respiratory-chain complexes impair oxidative phosphorylation (OXPHOS), leading to bioenergetic failure in vulnerable brain regions resulting in the characteristic bilateral, symmetric deep gray matter lesions observed on MRI. While this neuron-centric perspective helps explain regional vulnerability in LS, it overlooks the substantial mitochondrial demand of neural stem/progenitor cells (NSCs), which generate the majority of the brain cells during the embryonic and early postnatal periods. However, the in vivo consequences of sustained mitochondrial dysfunction during early neurogenesis remain poorly characterized. We leveraged the NDUFS4 knockout (KO) mouse, a well-established model of Complex I (CI) deficiency that recapitulates key clinical and neuropathological features of LS, to test whether sustained CI loss during early development disrupts NSC proliferation and lineage progression and secondarily impairs and white matter maturation. Gross neuroanatomical analysis revealed reduced brain weight and decreased hemispheric half-width. Immunohistochemistry showed an early reduction at postnatal day 14 (P14) in NSC and neuroblast populations within the SVZ, with the neurogenic defect progressing at later timepoints to impaired lineage advancement. To resolve cell type–specific effects of CI deficiency, we performed single-cell RNA sequencing (scRNA-seq) on the SVZ, which revealed a proliferation deficit in NSCs and intermediate progenitors. This finding was independently validated using neurosphere assays. Transcriptional programs and pathways linked to neurogenesis and oligodendrogenesis were significantly downregulated in KO neural progenitors. Although abundance of oligodendrocyte progenitors in the SVZ was not significantly altered, early and late myelin gene/protein expression was reduced, accompanied by decreased corpus callosum thickness. Together, these early neurodevelopmental defects in neurogenesis and callosal growth offer a potential mechanistic explanation for the developmental delays observed in LS. This work encourages future research into neurogenesis in other primary mitochondrial disorders and neurodegenerative disorders, especially those where developmental delays are a key feature.