The Role of PNKP in a Drosophila Model of Tauopathy
Alzheimer’s Disease (AD), along with several related neurodegenerative diseases called tauopathies, are characterized by neurofibrillary tangles (NFTs) consist of aggregated tau proteins in the brain, leading to cognitive dysfunctions and neurodegeneration. Accumulation of DNA damage has been found in AD brains, which is thought to underlie neurodegeneration. Recent studies from our collaborators have shown that AD patient brains have decreased activity of a DNA repair enzyme – polynucleotide kinase 3'-phosphatase (PNKP) – compared to healthy brains. Dysfunction of PNKP has been implicated in the pathophysiology of other neurodegenerative diseases, including Huntington’s Disease (HD) and spinocerebellar ataxia type 3 (SCA3). In a previous study on SCA3, increasing the expression of PNKP rescued DNA damage accumulation and neurodegenerative phenotypes in an animal model. However, the role of PNKP in context of tau-mediated neurodegeneration is unknown. In this study, we aimed to characterize the role of PNKP in tauopathies using a Drosophila model. We generated transgenic fly lines for wild-type Drosophila PNKP (dPNKP.WT) and several dPNKP mutants. Our results showed that overexpression of dPNKP.WT in human tau (hTau)-transgenic flies rescued the rough eye phenotype and motor dysfunction. These findings show that increasing PNKP expression ameliorates tau-mediated neurotoxicity in flies, suggesting that enhancing PNKP level or activity may be a therapeutic strategy for tauopathies including AD.