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 Ca from the endoplasmic reticulum (ER) induces Ca 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 Ca homeostasis and stabilize SOCE in YAC128 MSN cultures. We also detected a beneficial effect of this compound on the mitochondrial membrane potential. Since dysregulated Ca homeostasis is believed to be one of the pathological hallmarks of HD, this compound might be a lead structure for HD treatment.

Cause or compensation?—Altered neuronal Ca2+ handling in Huntington's disease

“…Interestingly, pharmacological SOC inhibition normalizes SPN dendritic spine loss in vitro and in vivo, 27 but does not normalize enhanced glutamate-mediated apoptosis. 28 Nonetheless, this suggests that neurodegeneration in HD is partly mediated by SOC upregulation, a compensatory response to ER Ca 2+ depletion ( Figure 1). In Parkinson's disease models, Ca 2+ influx through voltage-gated Ca 2+ channels causes loss of dendritic spines in D 2 receptor-expressing SPNs.…”

“…Experiments in YAC128‐derived cortical‐striatal cocultures suggest an enhanced IP3R leak that chronically depletes ER Ca 2+ stores. This elevates the store‐operated Ca 2+ channel (SOC) response, a mechanism by which ER Ca 2+ depletion is counteracted by specific, closely ER‐apposed, plasma membrane Ca 2+ channels . In aged YAC128 SPNs, SOC enhancement is mediated by upregulation of stromal interacting protein type‐2 (STIM2)—a Ca 2+ ‐sensitive, ER‐resident protein involved in SOC recruitment.…”

“…In aged YAC128 SPNs, SOC enhancement is mediated by upregulation of stromal interacting protein type‐2 (STIM2)—a Ca 2+ ‐sensitive, ER‐resident protein involved in SOC recruitment. Interestingly, pharmacological SOC inhibition normalizes SPN dendritic spine loss in vitro and in vivo, but does not normalize enhanced glutamate‐mediated apoptosis . Nonetheless, this suggests that neurodegeneration in HD is partly mediated by SOC upregulation, a compensatory response to ER Ca 2+ depletion (Figure ).…”

“…This elevates the store-operated Ca 2+ channel (SOC) response, a mechanism by which ER Ca 2+ depletion is counteracted by specific, closely ER-apposed, plasma membrane Ca 2+ channels. 27,28 In aged YAC128 SPNs, SOC enhancement is mediated by upregulation of stromal interacting protein type-2 (STIM2)-a Ca 2+ -sensitive, ER-resident protein involved in SOC recruitment. Interestingly, pharmacological SOC inhibition normalizes SPN dendritic spine loss in vitro and in vivo, 27 but does not normalize enhanced glutamate-mediated apoptosis.…”

Huntingtin-Associated Protein 1A Regulates Store-Operated Calcium Entry in Medium Spiny Neurons From Transgenic YAC128 Mice, a Model of Huntington’s Disease

“…Alterations of intracellular Ca 2+ signaling are believed to play a significant role in the pathogenesis of neurodegenerative disorders (Wojda et al, 2008 ; Bezprozvanny, 2009 ; Berridge, 2010 ; Riazantseva et al, 2012 ; Imamura et al, 2016 ; Alzheimer’s Association Calcium Hypothesis Workgroup, 2017 ; Surmeier et al, 2017 ), including HD (Wu et al, 2011 ; Czeredys et al, 2017 ; Kolobkova et al, 2017 ). One of the most ubiquitous pathways for Ca 2+ uptake is store-operated calcium entry (SOCE; Poggioli and Putney, 1982 ; Bouron et al, 2005 ; Prakriya and Lewis, 2015 ).…”