Contribuição das vias de reparo por excisão de bases e nucleotídeos no desenvolvimento de fenótipos neurodegenerativos nos modelos transgênicos de Caenorhabditis elegans

Abstract

Neurodegenerative diseases (NDs) are characterized by a progressive neuronal loss leading to motor or cognitive impairment. Although it is still not completely understood, NDs share many molecular mechanisms such as: oxidative stress, protein aggregation, deficiency of the ubiquitin–proteasome–autophagy system, mitochondrial dysfunction, impaired bioenergetics, dysfunction of neurotrophins and neuroinflammatory processes. The clinical observations that deficiencies in the nucleotide excision repair (NER) and base excision repair (BER) pathways cause human pathologies associated with neurological symptoms suggest that NER and BER might also play a critical role in chronic NDs. Here, we evaluated the deficiency of BER and NER pathways, especially EXO-3 and XPA-1, respectively, on the development of neurodegenerative phenotypes in Caenorhabditis elegans. EXO-3 and XPA-1 inhibition affected redox status by increasing ROS levels and up-regulating the expression of stress resistance related genes in a SKN-1 dependent manner. Similar results were found when APN1, XPC1 and CSB1 proteins were evaluated. EXO-3 and XPA-1 deficiency also activated the endoplasmic reticulum and mitochondrial unfolded protein response (UPR) and interfered in proteostasis as indicated by the reduced proteasome activity and proteasome subunits expression. Thesee alterations were associated with neurodegeneration of pan- and cholinergic-marked neurons. The neurodegeneration induced by EXO-3 and XPA-1 deficiency appears to be triggered by hyperactivation of the DNA damage sensor PARP-1 since this phenotype is rescued by PARP-1 inhibition. Inhibition of the apn-1, xpc-1 and csb1 genes in transgenic animals for Mal de Alzheimer and Hungtinton's disease accelerated neurodegenerative phenotypes, the most marked affect were in animals treted with csb-1(RNAi). Together, these results support a model where deficiency of NER and BER pathways plays an active role generating a network of stress signals sufficiently strong to trigger neurodegeneration.