Journal de la maladie d'Alzheimer et du parkinsonisme

Abstrait

Role of the Transcription Factor Nrf2 in Parkinson's Disease: New Insights

Isabel Lastres-Becker

Parkinson’s disease (PD) is a slow progressive neurodegenerative disorder associated with motor and nonmotor symptoms, with no neuroprotective therapies. This chronic disease is characterized by loss of dopaminergic neurons from the sustantia nigra pars compacta and the presence of cytoplasmic α-synuclein-positive inclusions called Lewy bodies in the surviving neurons. Although PD has unknown etiology, familiar forms of PD have bring new insights in the causes of the pathology. At the molecular level, PD is characterized by proteinopathy (aggregation of α-synuclein, proteasome dysfunction and autophagy alterations), oxidative stress (increased production of reactive oxidative species, iron accumulation and dopamine oxidation) and neuroinflammation (microgliosis, reactive astrogliosis and increased levels of pro-inflammatory cytokines). A link has been revealed between the transcription factor NRF2 and PD at genetic level, showing that a functional haplotype in the human NFE2L2 gene promoter of NRF2 with slightly increased transcriptional activity, is associated with decreased risk and with delayed age at onset of PD. Moreover, since NRF2 is able to modulate the three main hallmarks of PD, several pharmacological approaches have been used to determine the role of NRF2 targeting in the development of PD. In this review we are going to evaluate the possible role of NRF2 as a pharmacological target to modify the development of PD and how some compounds that have been promising in PD mice models could be transferred to the study in clinical trials.