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NEURONS ISOLATED FROM A53T SYNUCLEIN MICE DISPLAY DEFICITS IN SYNAPTIC DENISTY AND MITOCHONDRIAL FUNCTION THAT CAN BE ATTENUATED BY NRF2 ACTIVATION
Abstract
Aims
To investigate the role of NRF2 in synaptic plasticity and mitochondrial function in neurons isolated from the A53T alpha Synuclein (A53TSyn) mouse model of alpha synuclein accumulation. Our lab has demonstrated that loss of NRF2 results in diminished synaptic density and impaired mitochondrial function in healthy neurons and that its activation improves those endpoints. Here we explore the role NRF2 in a pathological context using A53TSyn neurons.
Methods
Hippocampal neurons from A53TSyn embryos or their wild-type (WT) littermates were grown in co-culture with glial cells for 4 weeks. In the final week neurons were exposed to either the NRF2 activating compound dimethyl fumarate (DMF) or the NRF2 inhibitor ML385. Dendritic arborization and spine density were quantified. Gene expression, mitochondrial function and levels of reactive oxygen species (ROS) were also analyzed in hippocampal A53TSyn and WT neurons treated with DMF or ML385.
Results
A53TSyn neurons displayed a progressive reduction in dendritic complexity over time in culture relative to WT neurons. This was accompanied by a decrease in spine density, diminished mitochondrial function and increased levels of ROS. DMF reversed all of these changes in the A53Tsyn neurons whereas ML385 exacerbated them. Similar effects of ML385 were observed in WT neurons although DMF treatment did elicit any effects.
Conclusions
These data show that NRF2 activation can attenuate alpha synuclein-related synaptic and mitochondrial dysfunction. Because of the strong correlation between synaptic density and cognitive function, these data suggest that NRF2 may be an important target to improve cognitive function in Parkinson’s disease.