Gene expression data from HD mutant and wild type ST14A cells, differentiated for 24 hours and treated with vehicle (DMSO) or with 5µM MIND4. Rattus norvegicus

Activation of cellular responses through the NRF2/KEAP1/ARE pathway is a promising therapeutic strategy to counter neurodegeneration. The present study identified a novel lead compound, MIND4, which induces canonical NRF2-dependent responses and is protective in primary neurons, neuronal slice cultures and a Drosophila model of Huntington’s disease (HD). In accord with the known anti-inflammatory effects of NRF2 activation, MIND4 and its structural analog, potently repressed an expression of inflammatory markers in activated microglial cells. MIND4 treatment significantly reduced levels of TNF-alpha in the cortex of symptomatic HD mice, demonstrating the neuroprotective anti-inflammatory potential of NRF2 activator in the CNS. A high affinity reversible binding of MIND4 ligands to the NRF2 inhibitor, KEAP1, was identified by a docking model and confirmed by mechanistic studies, suggesting a novel approach to activating the NRF2 pathway. The results offer a new therapeutic path for HD and other human diseases. Overall design: A total of 8 samples, HD mutant and wild type ST14A cells, stably expressing either a mutant expanded repeat (128Q) or wild type (26Q) 546 amino acid huntingtin fragment (a generous gift of E. Cattaneo) (Ehrlich et al., 2001)), 4 HD & 4 control, were used for drug treatment and array-based gene expression analysis. 4 samples, 2 HD and 2 Contol, were treated with 5µM MIND4 with each pair ran as replicates. The other 4 samples, 2 HD and 2 Contol, were treated with DMSO with each pair ran as replicates.