Partha Sarkar, PhD Associate Professor
4.214 Medical Research Building (MRB)
Tel: (409) 747-4559 | pssarkar@utmb.edu
Research Experts
Affiliations
Associate Professor, Department of Translational Neuroscience
Mitchell Center for Neurodegenerative Diseases | Sealy Center on Aging
Education and Training
Research Interests
The Sarkar laboratory studies how hereditary neurodegenerative diseases arise from failures of DNA repair in neurons. We have shown that huntingtin, ataxin-2, and TDP-43—proteins long studied for their capacity to aggregate—are functional components of the machinery that repairs damage in actively transcribed genes and mitochondrial DNA. Polyglutamine expansion and nuclear depletion disrupt these complexes, allowing damage to accumulate in the transcriptionally active genome before symptoms appear. This reframes Huntington's disease, the spinocerebellar ataxias, and FTD/ALS as genome-maintenance disorders and supports therapies that restore repair function rather than simply lower mutant protein. The lab works across biochemical reconstitution, patient-derived neurons, mice and Drosophila models, and human postmortem tissue, with support from NINDS, NEI, and the Hereditary Disease Foundation.
Polyglutamine ataxias.
Parallel work in SCA3 established that mutant ataxin-3 inactivates PNKP and triggers apoptosis through the DNA damage-response pathway, and that deficient classical NHEJ repair of transcribed genes is linked to SCA3 pathogenesis. Related work addresses motor coordination defects in SCA10 and the redox and metabolic consequences of polyQ expansion in ATXN3.
Repeat RNA toxicity and metabolic consequences.
A long-running line of work concerns myotonic dystrophy type 1, where expanded CUG RNA sequesters regulatory proteins, constitutively activates Notch signaling, suppresses PGC-1a, and drives oxidative stress and muscle degeneration. This connects to a broader question the lab pursues across models: how chronic DNA damage-response activation perturbs glucose transport, energy homeostasis, and inflammatory signaling, in HD and in diabetic tissue.
Approach
The lab combines biochemical reconstitution, mass spectrometry, proximity ligation, and super-resolution imaging to define repair complex composition and assembly, with patient-derived neurons, transgenic mouse models, Drosophila, and human postmortem brain tissue for validation. Cross-model conservation and patient tissue confirmation are built into project design rather than deferred to the end.
Translational direction
Two paths follow from mechanistic work. The first is restoration rather than reduction: delivering or stabilizing wild type protein function to rescue repair capacity, tested against the timing question of whether intervention must precede symptom onset. The second is targeting the repair machinery directly, including PNKP and the chromatin remodeling steps that license repair at transcribed loci. A patent on methods and compositions for treating neurologic disorders covers work in this area.
Support
Research in the laboratory has been supported by the National Institute of Neurological Disorders and Stroke, the National Eye Institute, the Hereditary Disease Foundation, the Mitchell Center for Neurodegenerative Diseases, and the John Sealy Memorial Endowment Fund. Current NIH support includes R01 NS130830, funded at the 1st percentile.
In summary, the Sarkar laboratory studies how hereditary neurodegenerative diseases arise from failures of DNA repair in neurons. We have shown that huntingtin, ataxin-2, and TDP-43, proteins long studied for their capacity to aggregate, are functional components of the machinery that repairs damage in actively transcribed genes and in mitochondrial DNA. Polyglutamine expansion and nuclear depletion disrupt these complexes, allowing damage to accumulate in the transcriptionally active genome before symptoms appear. This reframes Huntington's disease, the spinocerebellar ataxias, and FTD/ALS as disorders of genome maintenance, and argues for therapies that restore repair function rather than simply lowering the mutant protein. The lab works across biochemical reconstitution, patient-derived neurons, mouse and Drosophila models, and human postmortem tissue, with support from NINDS, NEI, and the Hereditary Disease Foundation.
Selected Publications
Bhat A, Lahane GP, Pandita RK, Bacolla A, Hoden B, Ramos KS, Krishnan S, Sarkar PS, Dhar A, Tainer JA, Pandita TK. (2026) Exploiting DNA damage tolerance for precision oncology. Trends Cancer. 2026 Sep 5: S2405-8033(26)001810. 1016/j. trecan.2026.08.003. PMID: 42697814.
Pendlebury DF, Truong K, Heath M, Reidling JC, Sarkar P.S., Thompson LM. PIAS1/PIAS4-Mediated SUMOylation of TDP-43 Is Induced by Oxidative Stress. bioRxiv [Preprint]. 2025 Nov 12:2025.11.10.687649. doi: 10.1101/2025.11.10.687649. PMID: 41292941; PMCID: PMC12642448.
Dagar G., Gupta A., Shankar A., Chauhan R., Macha M.A., Bhat A.A., Das D., Goyal R., Bhoriwal S., Pandita R.K., Prasad C.P., Sarkar P.S., Pandita T.K., Singh M. The future of cancer treatment: combining radiotherapy with immunotherapy. Front Mol Biosci. 2024 Jul 9; 11:1409300. doi: 10.3389/fmolb.2024.1409300. PMID: 39044839; PMCID: PMC11263218.
Bhat A., Bhan S., Kabiraj A., Pandita R.K., Ramos K.S., Nandi S., Sopori S., Sarkar P.S., Dhar A., Pandita S., Kumar R., Das C., Tainer J.A., Pandita T.K.; A predictive chromatin architecture nexus regulates transcription and DNA damage repair. J. Biol. Chem. 2025 Feb 11;301(3):108300. doi: 10.1016/j.jbc.2025.108300. PMID: 39947477.
Bhat MI, Pandita RK, Mushtaq A, Mir US, Saqib N, Sarkar P.S., Bhat A, Ramos KS, Pandita TK, Altaf M. Impact of Transposable Elements on DNA Double-Strand Break Repair and Genomic Stability. Mol Cell Biol. 2026;46(2):187-208. doi: 10.1080/10985549.2025.2594182. Epub 2026 Jan 11. PMID: 41521524.
Charaka V, Pandita RK, Tsai CL, Wang X, Chakraborty S, Ramos KS, Nandi S, Leonard F, Singh V, Sarkar P.S., Hunt CR, Tainer JA, Das C, Pandita TK. HP1β recruits RING1A to ubiquitinate histone H2A for BRCA1-mediated resection of double-stand breaks. iScience. 2025 Dec 30;29(2):114582. doi: 10.1016/j.isci.2025.114582. PMID: 41623472; PMCID: PMC12856345.
Sarkar P. S., Meola G., Zhang N. (2022): Editorial, Neurodegeneration: From Disease Mechanisms to Therapeutic Advancement, Front. Genet. Neurogenomics, 2022, DOI: 10.3389/fgene.2022.941846.
Pradhan S., Gao R., Bush K., Zhang N., Wairkar Y.P., Sarkar P.S. Polyglutamine Expansion in Huntingtin and Mechanism of DNA Damage Repair Defects in Huntington's Disease. Front Cell Neurosci. 2022 Apr 4; 16:837576. doi: 10.3389/fncel.2022.837576. PMID: 35444517; PMCID: PMC9013776.
Pradhan S, Gaikwad S, Tsai CL, Smith C, Zhang N, Bush K, Chakraborty A, Yuan S, Choudhary S, Keene CD, Ellerby LM, Hazra TK, La Spada AR, Wairkar YP, Ashizawa T, Tainer JA, Pandita TK, Thompson LM, Sarkar PS. Huntingtin preserves mitochondrial genome integrity in neurons, which is impaired in Huntington's disease. bioRxiv [Preprint]. 2025 Jul 24:2025.07.24.666629. doi: 10.1101/2025.07.24.666629. PMID: 40777236; PMCID: PMC12330591.
Pradhan S, Bush K, Zhang N, Pandita RK, Tsai CL, Smith C, Pandlebury DF, Gaikwad S, Leonard F, Nie L, Tao A, Russell W, Yuan S, Choudhary S, Ramos KS, Elferink C, Wairkar YP, Tainer JA, Thompson LM, Pandita TK, Sarkar PS. Chromatin remodeler BRG1 recruits huntingtin to repair DNA double-strand breaks in neurons. bioRxiv [Preprint]. 2024 Sep 20:2024.09.19.613927. doi: 10.1101/2024.09.19.613927. PMID: 39345557; PMCID: PMC11429940.