Loss of poly(ADP-ribose) glycohydrolase causes progressive neurodegeneration in Drosophila melanogaster

Poly(ADP-ribosyl)ation has been suggested to be involved in regulation of DNA repair, transcription, centrosome duplication, and chromosome stability. However, the regulation of degradation of poly(ADP-ribose) and its significance are not well understood. Here we report a loss-of-function mutant Drosophila with regard to poly(ADP-ribose) glycohydrolase, a major hydrolyzing enzyme of poly(ADP-ribose). The mutant lacks the conserved catalytic domain of poly(ADP-ribose) glycohydrolase, and exhibits lethality in the larval stages at the normal development temperature of 25degreesC. However, one-fourth of the mutants progress to the adult stage at 29degreesC but showed progressive neurodegeneration with reduced locomotor activity and a short lifespan. In association with this, extensive accumulation of poly(ADP-ribose) could be detected in the central nervous system. These results suggest that poly(ADPribose) metabolism is required for maintenance of the normal function of neuronal cells. The phenotypes observed in the parg mutant might be useful to understand neurodegenerative conditions such as the Alzheimer's and Parkinson's diseases that are caused by abnormal accumulation of substances in nervous tissue.

多聚（ADP - 核糖）化被认为参与DNA修复、转录、中心体复制和染色体稳定性的调控。然而，多聚（ADP - 核糖）降解的调控及其意义尚未被充分了解。在此我们报道一种关于多聚（ADP - 核糖）糖苷水解酶（多聚（ADP - 核糖）的一种主要水解酶）的功能缺失型果蝇突变体。该突变体缺失多聚（ADP - 核糖）糖苷水解酶的保守催化结构域，并且在25℃的正常发育温度下在幼虫阶段表现出致死性。然而，四分之一的突变体在29℃时能发育到成虫阶段，但表现出进行性神经退行性变，运动能力降低且寿命较短。与此相关的是，在中枢神经系统中可检测到多聚（ADP - 核糖）的大量积累。这些结果表明多聚（ADP - 核糖）代谢对于维持神经细胞的正常功能是必需的。在parg突变体中观察到的表型可能有助于理解由神经组织中物质异常积累导致的神经退行性疾病，如阿尔茨海默病和帕金森病。