| Full text | |
| Author(s): Show less - |
Sun, Congxin
;
Seranova, Elena
;
Cohen, Malkiel A.
;
Chipara, Miruna
;
Roberts, Jennie
;
Astuti, Dewi
;
Palhegyi, Adina M.
;
Acharjee, Animesh
;
Sedlackova, Lucia
;
Kataura, Tetsushi
;
Otten, Elsje G.
;
Panda, Prashanta K.
;
Lara-Reyna, Samuel
;
Korsgen, Miriam E.
;
Kauffman, Kevin J.
;
Huerta-Uribe, Alejandro
;
Zatyka, Malgorzata
;
Silva, Luiz F. S. E.
;
Torresi, Jorge
;
Zhang, Shupei
;
Hughes, Georgina W.
;
Ward, Carl
;
Kuechler, Erich R.
;
Cartwright, David
;
Trushin, Sergey
;
Trushina, Eugenia
;
Sahay, Gaurav
;
Buganim, Yosef
;
Lavery, Gareth G.
;
Gsponer, Joerg
;
Anderson, Daniel G.
;
Frickel, Eva-Maria
;
Rosenstock, Tatiana R.
;
Barrett, Timothy
;
Maddocks, Oliver D. K.
;
Tennant, Daniel A.
;
Wang, Haoyi
;
Jaenisch, Rudolf
;
Korolchuk, Viktor I.
;
Sarkar, Sovan
Total Authors: 40
|
| Document type: | Journal article |
| Source: | CELL REPORTS; v. 42, n. 5, p. 27-pg., 2023-05-30. |
| Abstract | |
Autophagy is a homeostatic process critical for cellular survival, and its malfunction is implicated in human diseases including neurodegeneration. Loss of autophagy contributes to cytotoxicity and tissue degenera-tion, but the mechanistic understanding of this phenomenon remains elusive. Here, we generated auto-phagy-deficient (ATG5-'-) human embryonic stem cells (hESCs), from which we established a human neuronal platform to investigate how loss of autophagy affects neuronal survival. ATG5-'- neurons exhibit basal cytotoxicity accompanied by metabolic defects. Depletion of nicotinamide adenine dinucleotide (NAD) due to hyperactivation of NAD-consuming enzymes is found to trigger cell death via mitochondrial depolarization in ATG5-'- neurons. Boosting intracellular NAD levels improves cell viability by restoring mitochondrial bioenergetics and proteostasis in ATG5-'- neurons. Our findings elucidate a mechanistic link between autophagy deficiency and neuronal cell death that can be targeted for therapeutic interventions in neurodegenerative and lysosomal storage diseases associated with autophagic defect. (AU) | |
| FAPESP's process: | 15/02041-1 - The role of lysine(K)-deacetylases on mitochondrial disorders's neuroprotection: perspectives of epigenetic therapy for amyotrophic lateral sclerosis and schizophrenia |
| Grantee: | Tatiana Rosado Rosenstock |
| Support Opportunities: | Research Grants - Young Investigators Grants |