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

Targeting the autophagy-NAD axis protects against cell death in Niemann-Pick type C1 disease models. Kataura T.*†, Sedlackova L.*, Sun C., Kocak G., Wilson N., Banks P., Hayat F., Trushin S., Trushina E., Maddocks O.D.K., Oblong J.E., Miwa S., Imoto M., Saiki S., Erskine D., Migaud M.E., Sarkar S.† and Korolchuk V.I.† Cell Death and Disease 15(5): 382 (2024). *Equal contribution; †Corresponding authors 

NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency. Sun C.*, Seranova E.*, Cohen M.A.*, Chipara M., Roberts J., Astuti D., Palhegyi A.M., Acharjee A., Sedlackova L., Kataura T., Otten E.G., Panda P.K., Reyna S.L., Korsgen M.E., Kauffman K.J., Huerta-Uribe A., Zatyka M., Silva L.F.S.E., Torresi J., Zhang S., Hughes G.W., Ward C., Kuechler E.R., Cartwright D., Trushin S., Trushina E., Sahay G., Buganim Y., Lavery G.G., Gsponer J., Anderson D.G., Frickel E.M., Rosenstock T.R., Barrett T., Maddocks O.D.K., Tennant D.A., Wang H., Jaenisch R., Korolchuk V.I.† and Sarkar S.† (2023) Cell Reports 42(5): 112372 (2023). *Equal contribution; †Corresponding authors 

Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome. Zatyka M.*, Rosenstock T.R.*, Sun C., Palhegyi A.M., Hughes G.W., Reyna S.L., Astuti D., Maio A.D., Sciauvaud A., Korsgen M.E., Stanulovic V., Kocak G., Rak M., Pourtoy-Brasselet S., Winter K., Varga T., Jarrige M., Polveche H., Correia J., Frickel E.M., Hoogenkamp M., Ward D.G., Aubry L., Barrett T. and Sarkar S. Stem Cell Reports 18(5): 1090-1106 (2023). *Equal contribution 

The autophagy-NAD axis in longevity and disease. Wilson N.*, Kataura T.*, Korsgen M.E., Sun C., Sarkar S.† and Korolchuk V.I.† Trends in Cell Biology 33(9): 788-802 (2023). *Equal contribution; †Corresponding authors 

Autophagy promotes cell survival by maintaining NAD levels. Kataura T.*, Sedlackova L.*, Otten E.G., Kumari R., Shapira D., Scialo F., Stefanatos R., Ishikawa K., Kelly G., Seranova E., Sun C., Maetzel D., Kenneth N., Trushin S., Zhang T., Trushina E., Bascom C.C., Tasseff R., Isfort R.J., Oblong J.E., Miwa S., Lazarou M., Jaenisch R., Imoto M., Saiki S., Papamichos-Chronakis M., Manjithaya R., Maddocks O.D.K., Sanz A., Sarkar S.† and Korolchuk V.I.† Developmental Cell 57(22): 2584-2598 (2022). *Equal contribution; †Corresponding authors 

Trehalose limits opportunistic mycobacterial survival during HIV co-infection by reversing HIV-mediated autophagy block. Sharma V., Makhdoomi M., Singh L., Kumar P., Khan N., Singh S., Verma H.N., Luthra K., Sarkar S. and Kumar D. Autophagy 17(2): 476-495 (2021).  

Human induced pluripotent stem cell models of neurodegenerative disorders for studying the biomedical implications of autophagy. Seranova E.*, Palhegyi A.M.*, Verma S., Dimova S., Lasry R., Naama M., Sun C., Barrett T., Rosenstock T.R., Kumar D., Cohen M.A., Buganim Y. and Sarkar S. Journal of Molecular Biology 432(8): 2754-2798 (2020). *Equal contribution  

Chemical screening approaches enabling drug discovery of autophagy modulators for biomedical applications in human diseases. Panda P.K.*, Fahrner A.*, Vats S., Seranova E., Sharma V., Chipara M., Desai P., Torresi J., Rosenstock T., Kumar D. and Sarkar S. Frontiers in Cell and Developmental Biology 7: 38 (2019). *Equal contribution  

Discovery of pan autophagy inhibitors identified by a high-throughput screen highlights macroautophagy as an evolutionarily conserved process across three eukaryotic kingdoms. Mishra P., Dauphinee A.N., Ward C., Sarkar S., Gunawardena A.H.L.A.N. and Manjithaya R. Autophagy 13(9): 1556-1572 (2017).  

Dysregulation of autophagy as a common mechanism in lysosomal storage diseases.Seranova E.*, Connolly K.J.*, Zatyka M., Rosenstock T.R., Barrett T., Tuxworth R.I.† and Sarkar S.† Essays in Biochemistry 61(6): 733-749 (2017). *Equal contribution; †Corresponding authors  

Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity.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. eLife 5: e11058 (2016).  

Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics. Kuo S.Y., Castoreno A.B., Aldrich L.N., Lassen K.G., Goel G., Dančík V., Kuballa P., Latorre I., Conway K.L., Sarkar S., Maetzel D., Jaenisch R., Clemons P.A., Schreiber S.L., Shamji A.F. and Xavier R.J. Proceedings of the National Academy of Sciences (PNAS), USA 112(31): E4281-E4287 (2015).  

Genetic and chemical correction of cholesterol accumulation and impaired autophagy in hepatic and neural cells derived from Niemann-Pick iPS cells.Maetzel D.*, Sarkar S.*, Wang H.*, Abi-Mosleh L., Xu P., Cheng A.W., Gao Q., Mitalipova M. and Jaenisch R. Stem Cell Reports 2(6): 866-880 (2014). *Equal contribution  

The developmental potential of iPSCs is greatly influenced by reprogramming factor selection.Buganim Y., Markoulaki S., van Wietmarschen N., Hoke H., Wu T., Ganz K., Akhtar-Zaidi B., He Y., Abraham B.J., Porubsky D., Kulenkampff E., Faddah D.A., Shi L., Gao Q., Sarkar S., Cohen M., Goldmann J., Nery J.R., Schultz M.D., Ecker J.R., Xiao A., Young R.A., Lansdorp P.M. and Jaenisch R. Cell Stem Cell 15(3): 295-309 (2014).  

Impaired autophagy in the lipid storage disorder Niemann-Pick type C1 disease.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. Cell Reports 5(5): 1302-1315 (2013).  

Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling.Sahay G., Querbes W., Alabi C., Eltoukhy A., Sarkar S., Zurenko C., Karagiannis E., Love K., Chen D., Zoncu R., Buganim Y., Schroeder A., Langer R. and Anderson D.G. Nature Biotechnology 31(7): 653-658 (2013).  

Direct reprogramming of fibroblasts into embryonic Sertoli-like cells by defined factors. Buganim Y., Itskovich E., Hu Y.C., Cheng A.W., Ganz K., Sarkar S., Fu D., Welstead G.G., Page D.C. and Jaenisch R. Cell Stem Cell 11(3): 373-386 (2012).  

Complex inhibitory effects of nitric oxide on autophagy. 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. Molecular Cell 43(1): 19-32 (2011).  

Lysosomal positioning coordinates cellular nutrient responses.Korolchuk, V., Saiki S., Lichtenberg M., Siddiqi F.H., Roberts E.A., Imarisio S., Jahreiss L., Sarkar S., Futter M., Menzies F.M., O’Kane C.J., Deretic V. and Rubinsztein D.C. Nature Cell Biology 13(4): 453-460 (2011).  

Laforin, the most common protein mutated in Lafora disease, regulates autophagy.Aguado C.*, Sarkar S.*, Korolchuk V., Criado-Garcia O., Vernia S., Boya P., Sanz P., de Cordoba S.R., Knecht E. and Rubinsztein D.C.
Human Molecular Genetics 19(14): 2867-2876 (2010). *Equal contribution  

Cystamine suppresses polyalanine toxicity in a mouse model of oculopharyngeal muscular dystrophy.Davies J.E., Rose C., Sarkar S. and Rubinsztein D.C. Science Translational Medicine2(34): 34ra40 (2010)  

Novel targets for Huntington's disease in an mTOR-independent autophagy pathway. 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. Nature Chemical Biology 4(5): 295-305 (2008). *Equal contribution  

A rational mechanism for combination treatment of Huntington's disease using lithium and rapamycin. Sarkar S., Krishna G., Imarisio S., Saiki S., O'Kane C.J. and Rubinsztein D.C. Human Molecular Genetics 17(2): 170-178 (2008).  

Small molecules enhance autophagy and reduce toxicity in Huntington’s disease models.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. Nature Chemical Biology 3(6): 331-338 (2007). *Equal contribution  

Trehalose, a novel mTOR-independent autophagy inducer, accelerates clearance of mutant huntingtin and alpha-synuclein.Sarkar S., Davies J.E., Huang Z., Tunnacliffe A. and Rubinsztein D.C. Journal of Biological Chemistry 282(8): 5641-5652 (2007).  

Lithium induces autophagy by inhibiting inositol monophosphatase.Sarkar S., Floto R.A., Berger Z., Imarisio S., Cordenier A., Pasco M., Cook L.J. and Rubinsztein D.C. Journal of Cell Biology 170(7): 1101-1111 (2005).