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Neuroprotective Effects of σ2R/TMEM97 Receptor Modulators in the Neuronal Model of Huntington's Disease
Jing Jin1, Nicolas Arbez1,2, James J Sahn3
1Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore Maryland, 21287, United States.
Insights
New research shows that targeting σ2R/TMEM97 with specific molecules can protect neurons from Huntington
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Huntington's disease (HD) is a fatal genetic neurodegenerative disorder.
- It is caused by an expanded CAG repeat in the Huntingtin (HTT) gene, leading to mutant huntingtin (mHTT) protein aggregation and neuronal death.
- Currently, no treatments can halt HD progression.
Purpose of the Study:
- To investigate the neuroprotective potential of σ2R/TMEM97-selective ligands in Huntington's disease models.
- To determine if targeting σ2R/TMEM97 can reduce mHTT-induced neuronal toxicity.
Main Methods:
- Synthesis and characterization of novel compounds targeting σ2R/TMEM97.
- Testing compound affinity and selectivity for σ2R/TMEM97 and other CNS targets.
- Assessment of neuroprotection in a cellular HD model using primary cortical neurons transfected with mHTT.
- Quantification of neuronal cell death via condensed nuclei staining.
Main Results:
- σ2R/TMEM97-selective ligands demonstrated high affinity and selectivity.
- These ligands significantly reduced neuronal toxicity induced by mHTT in the HD cell model.
- The observed neuroprotective effects were independent of σ1R modulation.
Conclusions:
- σ2R/TMEM97 modulators show promise in protecting neurons against mHTT-induced toxicity.
- Targeting σ2R/TMEM97 represents a potential novel therapeutic strategy for Huntington's disease.
- Further research into σ2R/TMEM97 ligands could lead to new HD treatments.
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 σ2R/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 σ2R/TMEM97-selective ligands decrease mHTT-induced neuronal toxicity. We first synthesized a set of compounds designed to bind to σ2R/TMEM97 and determined their binding profiles (Ki values) for σ2R/TMEM97 and other proteins in the central nervous system. Modulators with high affinity and selectivity for σ2R/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 σ2R/TMEM97 or σ1R 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, σ2R/TMEM97 modulators reduce the neuronal toxicity induced by mHTT, and their neuroprotective effects are not blocked by NE-100, a selective σ1R antagonist known to block neuroprotection by σ1R ligands. These results indicate for the first time that σ2R/TMEM97 modulators can protect neurons from mHTT-induced neuronal toxicity, suggesting that targeting σ2R/TMEM97 may lead to a novel therapeutic approach to treat patients with HD.
