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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Podrobná bibliografia
Vydané v:	Cell metabolism Ročník 24; číslo 4; s. 566
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 11.10.2016
Predmet:	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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Popis
Shrnutí:	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.
Bibliografia:	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