Autophagy in health and disease

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Group leader: Dr Sovan Sarkar

Overview

Autophagy is an intracellular degradation pathway essential for cell survival. Defective autophagy contributes to cellular degeneration whereas stimulating this process is of biomedical relevance in diverse diseases. Combining the knowledge of autophagy regulation, its dysfunction in diseases and potent chemical modulators in human disease-relevant cellular contexts will allow designing targeted therapy.

Our research group

Our research group aims to develop a pipeline originating from basic biology to drug discovery, and potentially translate the findings for biomedical applications. Using human embryonic stem cells (hESCs) and disease-specific human induced pluripotent stem cells (hiPSCs), we work on the regulation and therapeutic application of autophagy in relation to human physiology and diseases. We are particularly studying the molecular mechanisms of proteostasis including autophagy and mitophagy, and how deregulation of these intracellular degradation pathways causes neurodegeneration and cytotoxicity in other disease-relevant cellular systems.

We are also establishing chemical screening platforms for identifying potential therapeutic compounds improving cell viability in disease-affected human cells. Our work involves the cell biology of intracellular trafficking pathways such as autophagy, generation of hiPSC-based disease models, genome engineering in hESCs/hiPSCs, differentiation of hESCs/hiPSCs into disease-relevant cell types, and chemical screening approaches, amongst others.  Our work has implications in various physiological and pathological conditions, including development, immunity, cancer, ageing, longevity and neurodegeneration.

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Figure legend: (Left to right) hESC-derived MAP2-positive neurons; Endogenous LC3-positives autophagosomes in hESCs after stimulation of autophagy with starvation; hESC-derived Nestin and Pax6-positive neural precursors; Endogenous p62 (specific autophagy substrate) aggregates in disease fibroblasts with autophagy impairment.

Current projects

Broad research themes of the current projects include: 

  • The landscape and regulation of autophagy in human embryonic stem cells and in differentiated adult cell types.
  • The role of autophagy in cellular homeostasis, metabolism, neurodegeneration and ageing in human disease-relevant cell types.
  • Mechanisms of cellular degeneration and proteostasis in disease-affected human cell types derived from disease-specific induced pluripotent stem cells.
  • Drug discovery in human disease-affected cell types derived from disease-specific induced pluripotent stem cells.

More details can be found at Sovan Sarkar Lab website: https://www.sovansarkarlab.com/

Recent publications

  • Panda, P.K., Fahrner, A., Vats, S., Seranova, E., Sharma, V., Chipara, M., Desai, P., Torresi, J., Rosenstock, T., Kumar, D. and Sarkar, SChemical screening approaches enabling drug discovery of autophagy modulators for biomedical applications in human diseases. (2019)  Frontiers in Cell and Developmental Biology 7: 38.
  • Seranova, E., Ward, C., Chipara, M., Rosenstock, T.R. and Sarkar, S. In vitro screening platforms for identifying autophagy modulators in mammalian cells. (2019)  Methods in Molecular Biology 1880: 389-428.
  • Mishra, P., Dauphinee, A.N., Ward, C., Sarkar, S., Gunawardena, A.H.L.A.N. and Manjithaya, R. (2017) Discovery of pan autophagy modulators identified by a high-throughput screen highlights macroautophagy as an evolutionarily conserved process across three eukaryotic kingdoms. Autophagy 13(9): 1556-1572.
  • Carroll, B., Maetzel, D., Maddocks, O.D.K., Otten, G., Ratcliff, M., Smith, G.R., Dunlop, E.A., Passos, J.F., Davies, O.R., Jaenisch, R., Tee, A.R., Sarkar, S. and Korolchuk, V.I. (2016) Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity. eLife 5: e11058.
  • Maetzel, M.*, Sarkar, S.*, Wang, H.*, Abi-Mosleh, L., Xu, P., Cheng, A.W., Gao, Q., Mitalipova, M. and Jaenisch, R. (2014) Genetic and chemical correction of cholesterol accumulation and impaired autophagy in hepatic and neural cells derived from Niemann-Pick type C patient-specific iPS cells. Stem Cell Reports 2(6): 866-880. *Equal contribution
  • Sarkar, S., Carroll, B., Buganim, Y., Maetzel, D., Ng, A.H.M., Cassady, J.P., Cohen, M.A., Chakraborty, S., Wang, H., Spooner, E., Ploegh, H., Gsponer, J., Korolchuk, V.I. and Jaenisch, R. (2013) Impaired autophagy in the lipid storage disorder Niemann-Pick type C1 disease. Cell Reports 5(5): 1302-1315.
  • Sarkar, S. (2013) Regulation of autophagy by mTOR and mTOR-independent pathways: Autophagy dysfunction in neurodegenerative diseases and therapeutic application of autophagy enhancers. Biochemical Society Transactions 41(5): 1103-1130.
  • Sarkar, S., Korolchuk, V.I., Renna, M., Imarisio, S., Fleming, A., Williams, A., Garcia-Arencibia, M., Rose, C., Luo, S., Underwood, B.R., Kroemer, G., O'Kane, C.J. and Rubinsztein, D.C. (2011) Complex inhibitory effects of nitric oxide on autophagy. Molecular Cell 43(1): 19-32.
  • Williams, A.*, Sarkar, S.*, Cuddon, P.*, Ttofi, E.K., Saiki, S., Siddiqi, F.H., Jahreiss, L., Fleming, A., Pask, D., Goldsmith, P., O’Kane, C.J., Floto, R.A. and Rubinsztein, D.C. (2008) Novel targets for Huntington's disease in an mTOR-independent autophagy pathway. Nature Chemical Biology 4(5): 295-305. *Equal contribution
  • Sarkar, S.*, Perlstein, E.O.*, Imarisio, S., Pineau, S., Cordenier, A., Maglathlin, R.L., Webster, J.A., Lewis, T.A., O’Kane, C.J., Schreiber, S.L. and Rubinsztein, D.C. (2007) Small molecules enhance autophagy and reduce toxicity in Huntington’s disease models. Nature Chemical Biology 3(6): 331-338. *Equal contribution