One of the major questions that have driven my research interest throughout my scientific career is to understand what determines cell survival and what triggers the cell death process. My laboratory is currently trying to understand the balance between cell death and survival mechanisms in the context of cellular metabolism with particular emphasis on the NAD+ pathway. The molecule of interest is Sarm1 (sterile alpha and TIR contianing protein 1) which is a central regulator of programmed axonal degeneration.
One major focus of the lab is to understand the underlying mechanism of dopaminergic neuronal loss as often seen in Parkinson’s disease and the role of Sam1. We use both the cellular as well as the Drosophila model for our studies using standard cell biology and molecular biology techniques to address these questions. Mitochondria which are determinants of both ‘cell survival’ through the synthesis of ATP as well as ‘cell death’ by mediating apoptosis is the central theme to our ongoing projects. We are highly interested in how mitochondrial DAMPs emanating from the damaged mitochondria mediate the inflammatory responses as well as how it crosstalk with the autophagosome-lysosomal pathway (ALP) to regulate cell death/survival. Since NAD+ are one of the central regulators of cellular metabolism we are also trying to connect how the NAD+ consuming enzymes like PARP1, Sirtuins as well as the pro-neurodegenerative molecule Sarm1 plays a role in these processes.
The other project we are working on is to understand whether cancer cells utilize the deranged mitochondrial signaling for their survival and uncontrolled cellular proliferation. In this context, we have initiated a project on cervical cancer that are both HPV positive as well as HPV negative to understand how mitochondrial MAVS and SARM1 plays a role in evading viral immune response and help in the improved survival of these cells. We also seek to understand whether targeting the NAD+ pathway in these cells could help devise better therapeutic strategies targeting the tumor cells as opposed to the normal cells in the tumor microenvironment.
For more details on our neurobiology research and lab details please visit:
Staff Research Fellow, Federal Employee (FTE) at National Institute of Allergy and Infectious Diseases, NIH (2011-2012)
Post Doctoral Fellow, Laboratory of Viral Diseases, NIAID, NIH (2010-2011)
Post Doctoral Fellow, Molecular Oncology Program, Moffitt Cancer Center & Research Institute,(2006-2010)
PhD Biochemistry, Bose Institute, University of Calcutta (2006)
BSc Chemistry (University of Calcutta, 1998)
MSc Biochemistry (University of Calcutta, 2000)
Postdoctoral training I (2006-2010)
For my first postdoctoral training with Dr. Mark Alexandrow at Moffitt Cancer Center, USA, I identified an effect of Transforming Growth Factor b1 (TGF-β1), a growth suppressive factor, on the assembly and function of the pre-replication complex (pre-RC) proteins (Cdc6, Cdt1 and Mcm2-7) which play a pivotal role during the G1/S transition of the cell cycle. We showed that TGFβ signals affect pre-RC dynamics depending on the cell cycle stage in G1. TGF-β treatment in early G1, prior to pre-RC assembly caused suppression of the oncoprotein cMyc and inhibition of CycE-Cdk2 complexes. In contrast, Retinoblastoma protein (Rb) controls TGF-β1 arrest in late G1 via direct targeting of the MCM helicase, specifically through Mcm7. This study demonstrated that Rb-E2F complexes are not the sole determinant of the S-phase entry in mammalian cell cycle and propose a novel tumor suppressor role for Rb (Mukherjee et al, PLoS One, 2009; Mukherjee et al, Molecular and Cellular Biology, 2010).
Post Doctoral training II (2010-2012)
In my second postdoctoral training with Dr. Karin Peterson at Rocky Mountain Laboratories, NIH, USA, I continued my pursuit in understanding the effects of infection induced immune response in cell death and apoptosis. In order to understand the mechanisms of neurodegeneration during CNS infection, we used a model of La Crosses virus, a tri-segmented negative sense RNA encephalitis virus. We identified a novel role of SARM1 (sterile alpha and TIR-1 containing protein 1, a negative regulator of TLR signaling) in inducing neuronal death during virus infection. Furthermore, we identified an interaction of SARM1 with MAVS, an anti-viral signaling molecule at the mitochondria and demonstrated the delicate balance of a good signaling molecule like MAVS going awry during neurodegeneration inducing neuronal apoptosis. This study provided a novel mechanism for virus-induced neuronal death and revealed new targets for the development of therapeutics to treat encephalitic viral infections (Mukherjee et al, Immunity, 2013).
Ph.D training (2000-2006)
During my Ph.D work under the guidance of Prof. A.C. Ghose at Bose Institute, Kolkata, I applied cell biology and immunology based approaches to study the mechanisms of immunosuppression associated with visceral leishmaniasis (VL). We successfully established an intracardial model of VL infection in mice that followed the progressive nature of Leishmania infection as often encountered in human infection (Mukherjee et al, Immunology Letters, 2003). Our study also showed the significant implication of Leishmania infection on the peripheral organs like lymph nodes and suggested that cells that are not infected per se also showed impaired proliferative response and induction of apoptosis during L. donovani infection in vivo. The cellular anergy in VL could be attributed to dephosphorylation of key molecules in the lymphocyte signaling pathway leading to their inactivation and subsequent apoptosis (Mukherjee et al, Apoptosis, 2006).
Research / Administrative Experience+
My research interest lies in understanding the interactions between cellular signaling components and their role in disease pathogenesis. We are looking at the role of NAD+ metabolism in cell death and survival using two opposing models: the model for neurodegeneration where we need to preseve the health of the cell and a cancer model where we need to prevent the uncontrolled cellular proliferation. To connect these two systems we are trying to elucidate the role of mirochondria as central regulators that ultimately determine cellular fate and how the availability/loss of NAD+ as driven by different enxymes like PARP1, Sirtuins or Sarm1 affects mitochondrial health and metabolism. We are also looking at the details of the regulation of the autophagy-lysosomal pathway as disease drivers and how deregulation of this pathway by a defective mitochondrial signaling or loss of NAD+ may be used in targeted therapy in both neurodegenerative diseases like Parkinson's disease or cancers like cervical cancer.
Member Secretary, insitutional Biosafety Committee (IBSC)
Teaching / Other Experience+
Courses taught : 1. Undergraduate course in Physical Chemistry, Biochemistry
2. Post graduate course in Immunology
3. Post graduate course on Neurobiology
Post Graduate Supervision+
If you think science is fun and genuinely interested in learning about interactions between cellular proteins in disease pathology then please feel free to contact me.We currently have two open postions.
Current Lab Strength:
Malinki Sur: (The role of Sarm1 in the regulation of mitochondrial bioenergetics) (Ph.D student, INSPIRE Fellow (2013-present; in the process of thesis submission)
Puja Dey (Ph.D student, CSIR JRF, 2017-present) (Role of environmental toxins in age-associated neurodegeneration)
Ankita Sarkar (Ph.D Student, UGC JRF, 2017-present) (Role of PARP1 inhibitors in mitophagy and its effect on Sarm1 mediated cell death)
Sourav Dutta (Research Fellow, 2019) (Mitochondrial innate immune responses regulated by Sarm1)
Swati Bhat (Project Fellow, 2015-2017)
Sudipta Hazra (DBT-RA, 2014-2016)
Sur M, Dey P, Sarkar A, Bar S, Banerjee D, Bhat S and Mukherjee P*. (2018). Sarm1 induction and accompanying inflammatory response mediates age-dependent susceptibility to rotenone-induced neurotoxicity. Cell Death Discovery. 4:114. *Corresponding author
Mukherjee P, Winkler CW, Taylor KG, Woods TA, Nair V, Khan BA, Peterson KE. (2015). SARM1, Not MyD88, Mediates TLR7/TLR9-Induced Apoptosis in Neurons. J. Immunol. 196: 4913-21.
Madeddu S, Woods T.A, Mukherjee P, Sturdevant D, Butchi N.B. and Peterson K.E.. (2015). Identification of glial activation markers by comparison of transcriptome changes between astrocytes and microglia following innate immune stimulation.PLoS One, 10,:e0127336.
Mukherjee P, Tyson Woods, Roger Moore and Peterson KE. (2013). Innate immune-induced neuronal death during bunyavirus infection is mediated by MAVS induction of SARM1. Immunity, 38 (4):705 (Recommended by F1000)
Baker DG, Woods TA, Butchi NB, Morgan TM, Taylor RT, Sunyakumthorn P, Mukherjee P, Lubick KJ, Best SM, Peterson KE. (2013) Toll-like receptor 7 suppresses virus replication in neurons but does not affect viral pathogenesis in a mouse model of Langat virus infection. J Gen Virol. Feb; 94(Pt 2)
Mukherjee P, Butchi N.B., and Peterson K.E. (2012). Pattern Recognition Receptor activation of intrinsic brain cells and influence on viral neurovirulence. In Neuroinflammation:Pathogenesis, Mechanisms and Management. NOVA publishing (Chapter 12).
Rajdeep Banerjee, Sudeep Kumar, Abhik Sen, Ananda Mookerjee, Mukherjee P, Syamal Roy, Subrata Pal and Pradeep Das (2011). TGF-β-regulated tyrosine phosphatases induce lymphocyte apoptosis in Leishmania donovani-infected hamsters. Immunology and Cell Biology. 89:573
Mukherjee P, Winter SL, Alexandrow MG (2010). Cell Cycle Arrest by TGFb1 near G1/S is mediated by acute abrogation of preRC activation involving an Rb-MCM interaction. Mol. Cell. Biol. 30(3):845
Mukherjee P, Cao TV, Winter SL, Alexandrow MG (2009). Mammalian MCM loading in late-G1 coincides with Rb hyperphosphorylation and the transition to post-transcriptional control of progression into S-phase. PLoS One. 4:e5462
Mukherjee P, Majee SB, Ghosh S, Hazra B. (2009). Apoptosis-like death in Leishmania donovani promastigotes induced by diospyrin and its ethanolamine derivative. Int. J Antimicrob Agents. 34:596
Mukherjee P, Sen PC, Ghose AC. (2006). Lymph Node Cells from BALB/c Mice with Chronic Visceral Leishmaniasis Exhibiting Cellular Anergy and Apoptosis on Stimulation with PMA Plus Ionomycin: Involvement of Ser/Thr phosphatase. Apoptosis.11:2013
Mukherjee P, Ghosh AK, Ghose AC. (2003). Infection pattern and immune response in the spleen and liver of BALB/c mice intracardially infected with L. donovani amastigotes. Immunol. Lett. 86 (2): 131-8
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