NAD + Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair

Ataxia telangiectasia (A-T) is a rare autosomal recessive disease characterized by progressive neurodegeneration and cerebellar ataxia. A-T is causally linked to defects in ATM, a master regulator of the response to and repair of DNA double-strand breaks. The molecular basis of cerebellar atrophy an...

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Veröffentlicht in:Cell metabolism Jg. 24; H. 4; S. 566
Hauptverfasser: Fang, Evandro Fei, Kassahun, Henok, Croteau, Deborah L, Scheibye-Knudsen, Morten, Marosi, Krisztina, Lu, Huiming, Shamanna, Raghavendra A, Kalyanasundaram, Sumana, Bollineni, Ravi Chand, Wilson, Mark A, Iser, Wendy B, Wollman, Bradley N, Morevati, Marya, Li, Jun, Kerr, Jesse S, Lu, Qiping, Waltz, Tyler B, Tian, Jane, Sinclair, David A, Mattson, Mark P, Nilsen, Hilde, Bohr, Vilhelm A
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 11.10.2016
Schlagworte:
Animals
Ataxia Telangiectasia - pathology
Ataxia Telangiectasia Mutated Proteins - deficiency
Ataxia Telangiectasia Mutated Proteins - metabolism
Behavior, Animal
Caenorhabditis elegans - metabolism
Caenorhabditis elegans - ultrastructure
Cells, Cultured
Disease Models, Animal
DNA Repair - drug effects
Gene Knockdown Techniques
Health
Homeostasis - drug effects
Longevity - drug effects
Metabolomics
Mice
Mitophagy - drug effects
NAD - pharmacology
Neurons - drug effects
Neurons - metabolism
Phenotype
Phthalazines - pharmacology
Piperazines - pharmacology
Proteomics
Rats, Sprague-Dawley
Signal Transduction - drug effects
Sirtuin 1 - metabolism
ISSN:1932-7420, 1932-7420
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Zusammenfassung:Ataxia telangiectasia (A-T) is a rare autosomal recessive disease characterized by progressive neurodegeneration and cerebellar ataxia. A-T is causally linked to defects in ATM, a master regulator of the response to and repair of DNA double-strand breaks. The molecular basis of cerebellar atrophy and neurodegeneration in A-T patients is unclear. Here we report and examine the significance of increased PARylation, low NAD , and mitochondrial dysfunction in ATM-deficient neurons, mice, and worms. Treatments that replenish intracellular NAD reduce the severity of A-T neuropathology, normalize neuromuscular function, delay memory loss, and extend lifespan in both animal models. Mechanistically, treatments that increase intracellular NAD also stimulate neuronal DNA repair and improve mitochondrial quality via mitophagy. This work links two major theories on aging, DNA damage accumulation, and mitochondrial dysfunction through nuclear DNA damage-induced nuclear-mitochondrial signaling, and demonstrates that they are important pathophysiological determinants in premature aging of A-T, pointing to therapeutic interventions.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1932-7420
1932-7420
DOI:10.1016/j.cmet.2016.09.004