1. Neuroprotective Effects of σ 2 R/TMEM97 Receptor Modulators in the Neuronal Model of Huntington's Disease.
- Author
-
Jin J, Arbez N, Sahn JJ, Lu Y, Linkens KT, Hodges TR, Tang A, Wiseman R, Martin SF, and Ross CA
- Subjects
- Animals, Disease Models, Animal, Humans, Huntingtin Protein genetics, Huntingtin Protein metabolism, Membrane Proteins metabolism, Neurons metabolism, Receptors, Neurotransmitter metabolism, Receptors, sigma metabolism, Huntington Disease metabolism, Neurodegenerative Diseases metabolism, Neuroprotective Agents therapeutic use
- Abstract
Huntington's disease (HD) is a genetic neurodegenerative disease caused by an expanded CAG repeat in the Huntingtin ( HTT ) 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 σ
2 R/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 σ2 R/TMEM97-selective ligands decrease mHTT-induced neuronal toxicity. We first synthesized a set of compounds designed to bind to σ2 R/TMEM97 and determined their binding profiles ( Ki values) for σ2 R/TMEM97 and other proteins in the central nervous system. Modulators with high affinity and selectivity for σ2 R/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 σ2 R/TMEM97 or σ1 R 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, σ2 R/TMEM97 modulators reduce the neuronal toxicity induced by mHTT, and their neuroprotective effects are not blocked by NE-100, a selective σ1 R antagonist known to block neuroprotection by σ1 R ligands. These results indicate for the first time that σ2 R/TMEM97 modulators can protect neurons from mHTT-induced neuronal toxicity, suggesting that targeting σ2 R/TMEM97 may lead to a novel therapeutic approach to treat patients with HD.- Published
- 2022
- Full Text
- View/download PDF