title: Inactivation of PNKP by mutant ATXN3 triggers apoptosis by activating the DNA damage-response pathway in SCA3.
abstract: Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is an untreatable autosomal dominant neurodegenerative disease, and the most common such inherited ataxia worldwide. The mutation in SCA3 is the expansion of a polymorphic CAG tri-nucleotide repeat sequence in the C-terminal coding region of the ATXN3 gene at chromosomal locus 14q32.1. The mutant ATXN3 protein encoding expanded glutamine (polyQ) sequences interacts with multiple proteins in vivo, and is deposited as aggregates in the SCA3 brain. A large body of literature suggests that the loss of function of the native ATNX3-interacting proteins that are deposited in the polyQ aggregates contributes to cellular toxicity, systemic neurodegeneration and the pathogenic mechanism in SCA3. Nonetheless, a significant understanding of the disease etiology of SCA3, the molecular mechanism by which the polyQ expansions in the mutant ATXN3 induce neurodegeneration in SCA3 has remained elusive. In the present study, we show that the essential DNA strand break repair enzyme PNKP (polynucleotide kinase 3'-phosphatase) interacts with, and is inactivated by, the mutant ATXN3, resulting in inefficient DNA repair, persistent accumulation of DNA damage/strand breaks, and subsequent chronic activation of the DNA damage-response ataxia telangiectasia-mutated (ATM) signaling pathway in SCA3. We report that persistent accumulation of DNA damage/strand breaks and chronic activation of the serine/threonine kinase ATM and the downstream p53 and protein kinase C-δ pro-apoptotic pathways trigger neuronal dysfunction and eventually neuronal death in SCA3. Either PNKP overexpression or pharmacological inhibition of ATM dramatically blocked mutant ATXN3-mediated cell death. Discovery of the mechanism by which mutant ATXN3 induces DNA damage and amplifies the pro-death signaling pathways provides a molecular basis for neurodegeneration due to PNKP inactivation in SCA3, and for the first time offers a possible approach to treatment.
authors.affiliation: Department of Neurology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Rui
authors.initials: R
authors.lastname: Gao
authors.affiliation: Department of Neurology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; ICVS/3B's PT Government Associate Laboratory, Braga/Guimarặes, Portugal.
authors.forename: Anabela
authors.initials: A
authors.lastname: Silva-Fernandes
authors.affiliation: Department of Neurology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Xiang
authors.initials: X
authors.lastname: Fang
authors.affiliation: Department of Biomedical Engineering, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Adriana
authors.initials: A
authors.lastname: Paulucci-Holthauzen
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Arpita
authors.initials: A
authors.lastname: Chatterjee
authors.affiliation: Department of Neurology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Hang L
authors.initials: HL
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Jichi Medical School, Shimotsuke, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Matsuura
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Choudhary
authors.affiliation: Department of Neurology and McNight Brain Research Institute, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ashizawa
authors.affiliation: Department of Neurology, Albany Stratton VA Medical Center, Albany, New York, United States of America.
authors.forename: Arnulf H
authors.initials: AH
authors.lastname: Koeppen
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; ICVS/3B's PT Government Associate Laboratory, Braga/Guimarặes, Portugal.
authors.forename: Patricia
authors.initials: P
authors.lastname: Maciel
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Hazra
authors.affiliation: Department of Neurology, University of Texas Medical Branch, Galveston, Texas, United States of America; Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Partha S
authors.initials: PS
authors.lastname: Sarkar
mesh_terms: D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D000067699:Ataxin-3; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D045643:DNA Repair Enzymes / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D017827:Machado-Joseph Disease / Q000235:genetics* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000096:biosynthesis / Q000235:genetics*; D066329:Protein Aggregates / Q000235:genetics; D051745:Protein Kinase C-delta / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D066329:Protein Aggregates; D012097:Repressor Proteins; C530380:PNKP protein, human; D017853:Phosphotransferases (Alcohol Group Acceptor); C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051745:Protein Kinase C-delta; C092341:ATXN3 protein, human; D000067699:Ataxin-3; D045643:DNA Repair Enzymes