Dataset Information

Restoration of defective nuclear-mitochondrial DNA damage signaling suppresses neuropathology and extends healthspan in Ataxia telangiectasia across species

ABSTRACT: Ataxia-telangiectasia (A-T) is a disease characterized by genomic instability and severe neurodegeneration. It is caused by mutation in Ataxia-telangiectasia mutated gene (ATM) which encodes ATM, a key player in DNA double-strand break (DSB) repair. While many major symptoms of A-T (including hypersensitivity to ionizing radiation) are readily explained by its deficiency in repair of DSBs, the causes for the devastating cerebellar degeneration are still elusive. Here we report that in A-T, persistent unrepaired DNA damage signals from the nucleus to mitochondria (NM signaling) causing mitochondrial dysfunction leading to neurodegeneration. We find that depletion of NAD+ in A-T across species is likely due to persistent PARylation as inhibition of PARP1 restores NAD+levels.. NAD+ depletion affects the NAD+/SIRT1-PGC1α axis causing accumulation of damaged mitochondria through inhibition of mitophagy. Restoration of NAD+/SIRT1 activity through PARP1 inhibition, NAD+ supplementation or SIRT1 activation rescued the pathological and behavioral defects in A-T, suggesting a conserved role of the NAD+/SIRT1 pathway in inhibiting disease pathology. Notably, increasing the NAD+ levels extends lifespan and rescues A-T-specific behavioral defects in both C. elegans and mouse models of A-T. This is through induction of PINK1-DCT1-regulated mitophagy and DNA-PKcs-associated NHEJ DNA repair. Our results underscore the unified role of SIRT1 (Sir2.1) in mitochondrial health and highlight how Sir2.1 not only regulates mitochondrial biogenesis, but also induces PINK1-DCT1-dependent mitophagy. Our data support a model where by the two major theories on aging, DNA damage accumulation and mitochondrial dysfunction, conspire to promote neurodegeneration in A-T animal models and suggest that therapeutic interventions are possible in A-T and other untreatable DNA repair-deficient disorders.

OTHER RELATED OMICS DATASETS IN: PRJNA307122

INSTRUMENT(S): Q Exactive

ORGANISM(S): Caenorhabditis Elegans

SUBMITTER: Ravi Chand Bollineni

LAB HEAD: Bernd Thiede

PROVIDER: PXD003380 | Pride | 2018-06-25

REPOSITORIES: Pride

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Publications

NAD<sup>+</sup> Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair.

Fang Evandro Fei EF Kassahun Henok H Croteau Deborah L DL Scheibye-Knudsen Morten M Marosi Krisztina K Lu Huiming H Shamanna Raghavendra A RA Kalyanasundaram Sumana S Bollineni Ravi Chand RC Wilson Mark A MA Iser Wendy B WB Wollman Bradley N BN Morevati Marya M Li Jun J Kerr Jesse S JS Lu Qiping Q Waltz Tyler B TB Tian Jane J Sinclair David A DA Mattson Mark P MP Nilsen Hilde H Bohr Vilhelm A VA

Cell metabolism 20161001 4

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<sup>+</sup>, and mitochondrial dysfunction in ATM-deficient neurons, mice, ...[more]

PMID: 27732836

Similar Datasets

Project description:Mitochondrial dysfunction is a common feature in neurodegeneration and aging. We identify mitochondrial dysfunction in xeroderma pigmentosum group A (XPA), a nucleotide excision DNA repair disorder with severe neurodegeneration, in silico and in vivo. XPA deficient cells show defective mitophagy with excessive cleavage of PINK1 and increased mitochondrial membrane potential. The mitochondrial abnormalities appear to be caused by decreased activation of the NAD+-SIRT1-PGC-1? axis triggered by hyperactivation of the DNA damage sensor PARP1. This phenotype is rescued by PARP1 inhibition or by supplementation with NAD+ precursors that also rescue the lifespan defect in xpa-1 nematodes. Importantly, this pathogenesis appears common to ataxia-telangiectasia and Cockayne syndrome, two other DNA repair disorders with neurodegeneration, but absent in XPC, a DNA repair disorder without neurodegeneration. Our findings reveal a novel nuclear-mitochondrial cross-talk that is critical for the maintenance of mitochondrial health. Mice carrying WT, or CX (Csa-/-/Xpa-/-) alleles in a C57BL/6 background were maintained under standard laboratory conditions and allowed free access to water and control casein pelleted diet (Research Diets D12450B). At 3 months of age, 3 replicates of each of the CX and WT mice were given subcutaneous interscapular injections of 500 mg of Nicotinamide riboside/kg body weight/day or the equivalent volume of saline for 14 consecutive days at 4:00 pm. On day 15, the mice were sacrificed and half of the cerebellum was harvested for purification of mitochondria, with the left half snap-frozen, homogenized, and aliquoted for RNA isolation. Total RNA extraction was done using a TRIzol Plus RNA purification kit as per manufacturer’s protocol. Quality and quantity of the total RNA was tested using the Agilent 2100 Bio-Analyzer and RNA 6000 nano kits. The RNA was labeled using the standard Illumina protocol and hybed overnight to Mouse Ref-8 Illumina arrays. The arrays were scanned using the Beadstation 500 X from Illumina.

			Action	DRS
	150223_Hilde_N21A1.dat	Other
	150223_Hilde_N21A1.mgf	Mgf
	150223_Hilde_N21A1.raw	Raw
	150223_Hilde_N21A2.dat	Other
	150223_Hilde_N21A2.mgf	Mgf