PXD003380

PXD003380 is an original dataset announced via ProteomeXchange.

Title	Restoration of defective nuclear-mitochondrial DNA damage signaling suppresses neuropathology and extends healthspan in Ataxia telangiectasia across species
Description	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.
HostingRepository	PRIDE
AnnounceDate	2018-06-25
AnnouncementXML	Submission_2018-06-25_05:17:26.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ravi Chand Bollineni
SpeciesList	scientific name: Caenorhabditis elegans; NCBI TaxID: 6239;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2015-12-21 02:02:56	ID requested
⏵ 1	2018-06-25 05:17:27	announced

Fang EF, Kassahun H, Croteau DL, Scheibye-Knudsen M, Marosi K, Lu H, Shamanna RA, Kalyanasundaram S, Bollineni RC, Wilson MA, Iser WB, Wollman BN, Morevati M, Li J, Kerr JS, Lu Q, Waltz TB, Tian J, Sinclair DA, Mattson MP, Nilsen H, Bohr VA, Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair. Cell Metab, 24(4):566-581(2016) [pubmed]

curator keyword: Biological

submitter keyword: C.elegans,Aging,mass spectrometry,liquid chromatography

Bernd Thiede
contact affiliation	University of Oslo
contact email	bernd.thiede@ibv.uio.no
lab head
Ravi Chand Bollineni
contact affiliation	University of Oslo
contact email	r.c.bollineni@ibv.uio.no
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD003380
     1. Label: PRIDE project
     2. Name: Restoration of defective nuclear-mitochondrial DNA damage signaling suppresses neuropathology and extends healthspan in Ataxia telangiectasia across species