Tetrahydrocarbazoles decrease elevated SOCE in medium spiny neurons from transgenic YAC128 mice, a model of Huntington's disease.

Abstract

Huntington's disease (HD) is a hereditary neurodegenerative disease caused by a polyglutamine expansion within the huntingtin (HTT) gene. One of the cellular functions that is dysregulated in HD is store-operated calcium entry (SOCE), a process in which the depletion of Ca2+ from the endoplasmic reticulum (ER) induces Ca2+ influx from the extracellular space. We detected an enhanced activity of SOC channels in medium spiny neurons (MSNs) from YAC128 mice, a transgenic model of HD, and investigated whether this could be reverted by tetrahydrocarbazoles. The compound 6-bromo-N-(2-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride was indeed able to restore the disturbed Ca2+ homeostasis and stabilize SOCE in YAC128 MSN cultures. We also detected a beneficial effect of this compound on the mitochondrial membrane potential. Since dysregulated Ca2+ homeostasis is believed to be one of the pathological hallmarks of HD, this compound might be a lead structure for HD treatment.

• Authors: Magdalena Czeredys, Filip Maciag, Axel Methner, Jacek Kuznicki
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 483 Issue 4 Pg. 1194-1205 (Feb 19 2017) ISSN: 1090-2104 [Electronic] United States
• PMID: 27553284 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Carbazoles
• Culture Media
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Carbazoles (pharmacology)
• Cells, Cultured
• Culture Media
• Endoplasmic Reticulum (metabolism)
• Homeostasis
• Ion Transport
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Mice, Transgenic
• Neurons (drug effects, metabolism)