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| Autor(es): Mostrar menos - |
Sun, Congxin
;
Seranova, Elena
;
Cohen, Malkiel A.
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Chipara, Miruna
;
Roberts, Jennie
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Astuti, Dewi
;
Palhegyi, Adina M.
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Acharjee, Animesh
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Sedlackova, Lucia
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Kataura, Tetsushi
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Otten, Elsje G.
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Panda, Prashanta K.
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Lara-Reyna, Samuel
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Korsgen, Miriam E.
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Kauffman, Kevin J.
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Huerta-Uribe, Alejandro
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Zatyka, Malgorzata
;
Silva, Luiz F. S. E.
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Torresi, Jorge
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Zhang, Shupei
;
Hughes, Georgina W.
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Ward, Carl
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Kuechler, Erich R.
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Cartwright, David
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Trushin, Sergey
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Trushina, Eugenia
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Sahay, Gaurav
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Buganim, Yosef
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Lavery, Gareth G.
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Gsponer, Joerg
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Anderson, Daniel G.
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Frickel, Eva-Maria
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Rosenstock, Tatiana R.
;
Barrett, Timothy
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Maddocks, Oliver D. K.
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Tennant, Daniel A.
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Wang, Haoyi
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Jaenisch, Rudolf
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Korolchuk, Viktor I.
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Sarkar, Sovan
Número total de Autores: 40
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| Tipo de documento: | Artigo Científico |
| Fonte: | CELL REPORTS; v. 42, n. 5, p. 27-pg., 2023-05-30. |
| Resumo | |
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) | |
| Processo FAPESP: | 15/02041-1 - O papel das lisinas(K)-deacetilases para a neuroproteção de desordens mitocondriais: perspectivas de terapia epigenética para a esclerose lateral amiotrófica e esquizofrenia |
| Beneficiário: | Tatiana Rosado Rosenstock |
| Modalidade de apoio: | Auxílio à Pesquisa - Jovens Pesquisadores |