Inactivation of PNKP by Mutant ATXN3 Triggers Apoptosis by Activating the DNA Damage-Response Pathway in SCA3

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Spinocerebellar ataxia type 3 (SCA3) is an untreatable neurodegenerative disease, and the most common dominantly inherited ataxia worldwide. SCA3 is caused by expansion of a CAG tri-nucleotide repeat sequence in the ATXN3 gene’s coding region. The expanded CAG sequences encode a run of the amino acid glutamine; the mutant ATXN3 interacts with multiple proteins in vivo to create insoluble aggregates in SCA3 brains. It is thought that the loss of function of the aggregated proteins contributes to cellular toxicity and neurodegeneration in SCA3. Despite significant progress in understanding SCA3’s etiology, the molecular mechanism by which the mutant protein triggers the death of neurons in SCA3 brains remains unknown. We now report that the mutant ATXN3 protein interacts with and inactivates PNKP (polynucleotide kinase 3’-phosphatase), an essential DNA strand break repair enzyme. This inactivation results in persistent accumulation of DNA damage, and chronic activation of the DNA damage-response ATM signaling pathway in SCA3. Our work suggests that persistent DNA damage/strand breaks and chronic activation of ATM trigger neuronal death in SCA3. Discovery of the mechanism by which mutant ATXN3 induces DNA damage and amplifies the pro-death pathways provides a molecular basis for neurodegeneration in SCA3, and perhaps ultimately for its treatment.

Vyšlo v časopise: Inactivation of PNKP by Mutant ATXN3 Triggers Apoptosis by Activating the DNA Damage-Response Pathway in SCA3. PLoS Genet 11(1): e32767. doi:10.1371/journal.pgen.1004834
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004834

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