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NAD Depletion Mediates Cytotoxicity in Human Neurons With Autophagy Deficiency

126 Pages Posted: 8 Mar 2022 Publication Status: Under Review

See all articles by Congxin Sun

Congxin Sun

University of Birmingham

Elena Seranova

University of Birmingham

Malkiel A. Cohen

Massachusetts Institute of Technology (MIT) - Whitehead Institute for Biomedical Research

Miruna Chipara

University of Birmingham

Jennie Roberts

University of Birmingham - Institute of Metabolism and Systems Research

Adina M. Palhegyi

University of Birmingham

Animesh Acharjee

University of Birmingham

Lucia Sedlackova

Newcastle University

Tetsushi Kataura

Newcastle University - Biosciences Institute

Elsje G. Otten

University of Cambridge - MRC Laboratory of Molecular Biology

Prashanta K. Panda

University of Birmingham

Kevin J. Kauffman

affiliation not provided to SSRN

Alejandro Huerta-Uribe

University of Glasgow

Malgorzata Zatyka

University of Birmingham

Luiz F.S.E. Silva

University of Birmingham

Jorge Torresi

University of Birmingham

Shupei Zhang

Massachusetts Institute of Technology (MIT) - Whitehead Institute for Biomedical Research

Carl Ward

University of Birmingham

Erich R. Kuechler

affiliation not provided to SSRN

David Cartwright

University of Birmingham

Sergey Trushin

affiliation not provided to SSRN

Eugenia Trushina

affiliation not provided to SSRN

Gaurav Sahay

Oregon State University

Yosef Buganim

affiliation not provided to SSRN

Gareth G. Lavery

Nottingham Trent University

Joerg Gsponer

University of British Columbia (UBC) - Department of Biochemistry and Molecular Biology

Daniel G. Anderson

Massachusetts Institute of Technology (MIT) - Institute for Medical Engineering and Science

Tatiana R. Rosenstock

University of Birmingham

Timothy Barrett

University of Birmingham

Oliver D.K. Maddocks

University of Glasgow

Daniel A. Tennant

University of Birmingham - Institute of Metabolism and Systems Research

Haoyi Wang

affiliation not provided to SSRN

Rudolf Jaenisch

Massachusetts Institute of Technology (MIT) - Whitehead Institute for Biomedical Research

Viktor I. Korolchuk

Newcastle University

Sovan Sarkar

University of Birmingham - Institute of Cancer and Genomic Sciences

More...

Abstract

Autophagy is a homeostatic process critical for cellular survival, and its malfunction is implicated in myriad human diseases including neurodegeneration. Loss of autophagy contributes to cytotoxicity and tissue degeneration, but the mechanistic understanding of this phenomenon remains elusive. Here we generated autophagy-deficient (ATG5–/–) human embryonic stem cells (hESCs), from which we established human neuronal platform to investigate how loss of autophagy affects neuronal survival. ATG5–/– neurons exhibited basal cytotoxicity accompanied by metabolic defects. Depletion of nicotinamide adenine dinucleotide (NAD) due to hyperactivation of NAD-consuming enzymes was found to trigger cell death via mitochondrial depolarisation in ATG5–/– neurons. Boosting intracellular NAD levels improved cell viability by restoring mitochondrial membrane potential in ATG5–/– neurons. Our findings elucidate a mechanistic link between autophagy deficiency and neuronal cell death that could be targeted for therapeutic interventions in neurodegenerative and lysosomal storage diseases associated with autophagic defect.

Keywords: autophagy, cell death, cell survival, human embryonic stem cell, neuron, mitochondria, NAD, NADases, L-tryptophan, nicotinamide

Suggested Citation

Sun, Congxin and Seranova, Elena and Cohen, Malkiel A. and Chipara, Miruna and Roberts, Jennie and Palhegyi, Adina M. and Acharjee, Animesh and Sedlackova, Lucia and Kataura, Tetsushi and Otten, Elsje G. and Panda, Prashanta K. and Kauffman, Kevin J. and Huerta-Uribe, Alejandro and Zatyka, Malgorzata and Silva, Luiz F.S.E. and Torresi, Jorge and Zhang, Shupei and Ward, Carl and Kuechler, Erich R. and Cartwright, David and Trushin, Sergey and Trushina, Eugenia and Sahay, Gaurav and Buganim, Yosef and Lavery, Gareth G. and Gsponer, Joerg and Anderson, Daniel G. and Rosenstock, Tatiana R. and Barrett, Timothy and Maddocks, Oliver D.K. and Tennant, Daniel A. and Wang, Haoyi and Jaenisch, Rudolf and Korolchuk, Viktor I. and Sarkar, Sovan, NAD Depletion Mediates Cytotoxicity in Human Neurons With Autophagy Deficiency. Available at SSRN: https://ssrn.com/abstract=4052958 or http://dx.doi.org/10.2139/ssrn.4052958
This version of the paper has not been formally peer reviewed.

Congxin Sun

University of Birmingham ( email )

Elena Seranova

University of Birmingham ( email )

Malkiel A. Cohen

Massachusetts Institute of Technology (MIT) - Whitehead Institute for Biomedical Research ( email )

455 Main Street
Cambridge, MA 02142
United States

Miruna Chipara

University of Birmingham ( email )

Edgbaston, B15 2TT
United Kingdom

Jennie Roberts

University of Birmingham - Institute of Metabolism and Systems Research

Edgbaston, B15 2TT
United Kingdom

Adina M. Palhegyi

University of Birmingham ( email )

Edgbaston, B15 2TT
United Kingdom

Animesh Acharjee

University of Birmingham ( email )

Edgbaston, B15 2TT
United Kingdom

Lucia Sedlackova

Newcastle University ( email )

Tetsushi Kataura

Newcastle University - Biosciences Institute ( email )

Elsje G. Otten

University of Cambridge - MRC Laboratory of Molecular Biology ( email )

Cambridge Biomedical Campus
Francis Crick Avenue
Cambridge, CB2 0QH
United Kingdom

Prashanta K. Panda

University of Birmingham ( email )

Edgbaston, B15 2TT
United Kingdom

Kevin J. Kauffman

affiliation not provided to SSRN ( email )

No Address Available

Alejandro Huerta-Uribe

University of Glasgow ( email )

Adam Smith Business School
Glasgow, G12 8LE
United Kingdom

Malgorzata Zatyka

University of Birmingham ( email )

Edgbaston, B15 2TT
United Kingdom

Luiz F.S.E. Silva

University of Birmingham ( email )

Edgbaston, B15 2TT
United Kingdom

Jorge Torresi

University of Birmingham ( email )

Edgbaston, B15 2TT
United Kingdom

Shupei Zhang

Massachusetts Institute of Technology (MIT) - Whitehead Institute for Biomedical Research ( email )

455 Main Street
Cambridge, MA 02142
United States

Carl Ward

University of Birmingham ( email )

Erich R. Kuechler

affiliation not provided to SSRN ( email )

No Address Available

David Cartwright

University of Birmingham ( email )

Edgbaston, B15 2TT
United Kingdom

Sergey Trushin

affiliation not provided to SSRN ( email )

No Address Available

Eugenia Trushina

affiliation not provided to SSRN ( email )

No Address Available

Gaurav Sahay

Oregon State University ( email )

Bexell Hall 200
Corvallis, OR 97331
United States

Yosef Buganim

affiliation not provided to SSRN

Gareth G. Lavery

Nottingham Trent University ( email )

Burton Street
Nottingham NG1 4BU, NG1 4LN
United Kingdom

Joerg Gsponer

University of British Columbia (UBC) - Department of Biochemistry and Molecular Biology ( email )

Vancouver, British Columbia
Canada

Daniel G. Anderson

Massachusetts Institute of Technology (MIT) - Institute for Medical Engineering and Science ( email )

Cambridge, MA
United States

Tatiana R. Rosenstock

University of Birmingham ( email )

Edgbaston, B15 2TT
United Kingdom

Timothy Barrett

University of Birmingham ( email )

Edgbaston, B15 2TT
United Kingdom

Oliver D.K. Maddocks

University of Glasgow ( email )

Adam Smith Business School
Glasgow, G12 8LE
United Kingdom

Daniel A. Tennant

University of Birmingham - Institute of Metabolism and Systems Research ( email )

Birmingham
United Kingdom

Haoyi Wang

affiliation not provided to SSRN ( email )

No Address Available

Rudolf Jaenisch

Massachusetts Institute of Technology (MIT) - Whitehead Institute for Biomedical Research ( email )

455 Main Street
Cambridge, MA 02142
United States

Viktor I. Korolchuk

Newcastle University ( email )

Newcastle upon Tyne
NE1 7RU
United Kingdom

Sovan Sarkar (Contact Author)

University of Birmingham - Institute of Cancer and Genomic Sciences ( email )

Edgbaston
Birminham, Birmingham B152TT
United Kingdom

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