Isabel Lastres-Becker
Autonomous University of Madrid, Spain
Title: Repurposing the NRF2 activator dimethyl fumarate as therapy against synucleinopathy in Parkinson’s disease
Biography
Biography: Isabel Lastres-Becker
Abstract
This preclinical study was aimed at determining if pharmacological targeting of transcription factor NRF2 might provide a disease modifying therapy in the animal model of Parkinson’s disease (PD) that best reproduces the main hallmark of this pathology, i.e. α-synucleinopathy, and associated events including nigral dopaminergic cell death, oxidative stress and neuroinflammation. Pharmacological activation of NRF2 was at the basal ganglia by repurposing dimethyl fumarate (DMF), a drug already in use for the treatment of multiple sclerosis, leading to up-regulation of a battery of cytoprotective genes. Daily oral gavage of DMF protected nigral dopaminergic neurons against α-SYN toxicity and decreased astrocytosis and microgliosis after 1, 3 and 8 weeks from stereotaxic delivery to the ventral midbrain of recombinant adeno-associated viral vector expressing human α-synuclein. This protective effect was not observed in Nrf2-knockout mice. In vitro studies indicated that this neuroprotective effect was correlated with altered regulation of autophagy markers p62, LC3 and LAMP2 in MN9D, BV2 and IMA 2.1 and with a shift in microglial dynamics towards a less pro-inflammatory and more wound-healing phenotype. In postmortem samples of PD patients, the cytoprotective proteins associated with NRF2 expression, NQO1 and SQSTM1/p62, were partly sequestered in Lewy bodies, suggesting impaired neuroprotective capacity of the NRF2 signature. These experiments provide a compelling rationale for targeting NRF2 with DMF as a therapeutic strategy to reinforce endogenous brain defense mechanisms against PD-associated synucleinopathy.