Neuroprotective Effects of σR/TMEM97 Receptor Modulators in the Neuronal Model of Huntington's Disease.

Huntington's disease (HD) is a genetic neurodegenerative disease caused by an expanded CAG repeat in the () gene that encodes for an expanded polyglutamine (polyQ) repeat in exon-1 of the human mutant huntingtin (mHTT) protein. The presence of this polyQ repeat results in neuronal degeneration, for which there is no cure or treatment that modifies disease progression. In previous studies, we have shown that small molecules that bind selectively to σR/TMEM97 can have significant neuroprotective effects in models of Alzheimer's disease, traumatic brain injury, and several other neurodegenerative diseases. In the present work, we extend these investigations and show that certain σR/TMEM97-selective ligands decrease mHTT-induced neuronal toxicity. We first synthesized a set of compounds designed to bind to σR/TMEM97 and determined their binding profiles ( values) for σR/TMEM97 and other proteins in the central nervous system. Modulators with high affinity and selectivity for σR/TMEM97 were then tested in our HD cell model. Primary cortical neurons were cultured in vitro for 7 days and then co-transfected with either a normal HTT construct (Htt N-586-22Q/GFP) or the mHTT construct Htt-N586-82Q/GFP. Transfected neurons were treated with either σR/TMEM97 or σR modulators for 48 h. After treatment, neurons were fixed and stained with Hoechst, and condensed nuclei were quantified to assess cell death in the transfected neurons. Significantly, σR/TMEM97 modulators reduce the neuronal toxicity induced by mHTT, and their neuroprotective effects are not blocked by NE-100, a selective σR antagonist known to block neuroprotection by σR ligands. These results indicate for the first time that σR/TMEM97 modulators can protect neurons from mHTT-induced neuronal toxicity, suggesting that targeting σR/TMEM97 may lead to a novel therapeutic approach to treat patients with HD.