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NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency.

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 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 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.

SUBMITTER: Sun C

PROVIDER: S-EPMC10556436 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency.

Sun Congxin C Seranova Elena E Cohen Malkiel A MA Chipara Miruna M Roberts Jennie J Astuti Dewi D Palhegyi Adina M AM Acharjee Animesh A Sedlackova Lucia L Kataura Tetsushi T Otten Elsje G EG Panda Prashanta K PK Lara-Reyna Samuel S Korsgen Miriam E ME Kauffman Kevin J KJ Huerta-Uribe Alejandro A Zatyka Malgorzata M Silva Luiz F S E LFSE Torresi Jorge J Zhang Shupei S Hughes Georgina W GW Ward Carl C Kuechler Erich R ER Cartwright David D Trushin Sergey S Trushina Eugenia E Sahay Gaurav G Buganim Yosef Y Lavery Gareth G GG Gsponer Joerg J Anderson Daniel G DG Frickel Eva-Maria EM Rosenstock Tatiana R TR Barrett Timothy T Maddocks Oliver D K ODK Tennant Daniel A DA Wang Haoyi H Jaenisch Rudolf R Korolchuk Viktor I VI Sarkar Sovan S

Cell reports 20230421 5

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 degeneration, but the mechanistic understanding of this phenomenon remains elusive. Here, we generated autophagy-deficient (ATG5<sup>-/-</sup>) human embryonic stem cells (hESCs), from which we established a human neuronal platform to investigate how loss of autophagy affects neuronal survival. ...[more]

PMID: 37086404

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Project description:Alzheimer's disease (AD) is an age-related neurodegenerative condition and the most common type of dementia, characterised by pathological accumulation of extracellular plaques and intracellular neurofibrillary tangles that mainly consist of amyloid-β (Aβ) and hyperphosphorylated tau aggregates, respectively. Previous studies in mouse models with a targeted knock-out of the microtubule-associated protein tau (Mapt) gene demonstrated that Aβ-driven toxicity is tau-dependent. However, human cellular models with chronic tau lowering remain unexplored. In this study, we generated stable tau-depleted human induced pluripotent stem cell (iPSC) isogenic panels from two healthy individuals using CRISPR-Cas9 technology. We then differentiated these iPSCs into cortical neurons in vitro in co-culture with primary rat cortical astrocytes before conducting electrophysiological and imaging experiments for a wide range of disease-relevant phenotypes. Both AD brain derived and recombinant Aβ were used in this study to elicit toxic responses from the iPSC-derived cortical neurons. We showed that tau depletion in human iPSC-derived cortical neurons caused considerable reductions in neuronal activity without affecting synaptic density. We also observed neurite outgrowth impairments in two of the tau-depleted lines used. Finally, tau depletion protected neurons from adverse effects by mitigating the impact of exogenous Aβ-induced hyperactivity, deficits in retrograde axonal transport of mitochondria, and neurodegeneration. Our study established stable human iPSC isogenic panels with chronic tau depletion from two healthy individuals. Cortical neurons derived from these iPSC lines showed that tau is essential in Aβ-driven hyperactivity, axonal transport deficits, and neurodegeneration, consistent with studies conducted in Mapt-/- mouse models. These findings highlight the protective effects of chronic tau lowering strategies in AD pathogenesis and reinforce the potential in clinical settings. The tau-depleted human iPSC models can now be applied at scale to investigate the involvement of tau in disease-relevant pathways and cell types.

Dataset Information

NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency.

Publications

NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency.

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