Patient-Specific iPSC-Based Models of Huntington’s Disease as a Tool to Study Store-Operated Calcium Entry Drug Targeting

Abstract

Neurodegenerative pathologies are among the most serious and socially significant problems of modern medicine, along with cardiovascular and oncological diseases. Several attempts have been made to prevent neuronal death using novel drugs targeted to the cell calcium signaling machinery, but the lack of adequate models for screening markedly impairs the development of relevant drugs. A potential breakthrough in this field is offered by the models of hereditary neurodegenerative pathologies based on endogenous expression of mutant proteins in neurons differentiated from patient-specific induced pluripotent stem cells (iPSCs). Here, we study specific features of store-operated calcium entry (SOCE) using an iPSCs-based model of Huntington’s disease (HD) and analyze the pharmacological effects of a specific drug targeted to the calcium channels. We show that SOCE in gamma aminobutyric acid-ergic striatal medium spiny neurons (GABA MSNs) was mediated by currents through at least two different channel groups, ICRAC and ISOC. Both of these groups were upregulated in HD neurons compared with the wild-type neurons. Thapsigargin-induced intracellular calcium store depletion in GABA MSNs resulted in predominant activation of either ICRAC or ISOC. The potential anti-HD drug EVP4593, which was previously shown to have neuroprotective activity in different HD models, affected both ICRAC and ISOC.

In vitro Models of Neurodegenerative Diseases

“…It is defined by deep gray matter volume loss caused by the destruction of neurons in the substantia nigra, leading to dopamine deficiency in the basal ganglia. PD affects 1-2% Lotharius et al, 2005;Van Vliet et al, 2008;Zhang et al, 2014;Smirnova et al, 2016;Harischandra et al, 2019;Taylor-Whiteley et al, 2019Tan et al, 2018 Amyotrophic lateral sclerosis Pansarasa et al, 2018Chen et al, 2014Fujimori et al, 2018Dimos et al, 2008Burkhardt et al, 2013;Sareen et al, 2013Smith et al, 2015Krencik et al, 2017;Osaki et al, 2018. Huntington's disease Bidollari et al, 2018Szlachcic et al, 2017An et al, 2012Camnasio et al, 2012;Juopperi et al, 2012;Nekrasov et al, 2016;Vigont et al, 2018;Mehta et al, 2018Virlogeux et al, 2018 Spinal muscular atrophy Not available Not available Ebert et al, 2009;Fuller et al, 2015;Zhang et al, 2017a;Valetdinova et al, 2019. Hor et al, 2018 Spinocerebellar ataxia Kumar D. et al, 2018;Maguire et al, 2019Wang et al, 2015Xia et al, 2013Marthaler et al, 2016;Nayler et al, 2017;Sun et al, 2018;Chuang et al, 2019;…”

Dysregulation of Neuronal Calcium Signaling via Store-Operated Channels in Huntington's Disease

“…These currents were upregulated compared with wildtype iPSC-based GABAergic MSNs. Thapsigargin-induced intracellular Ca 2+ store depletion in iPSC-based GABAergic MSNs resulted in the simultaneous activation of both I CRAC and I SOC (Vigont et al, 2018 ).…”

“…This compound also potently stabilized SOC entry in HD iPSC-based GABAergic MSNs (Nekrasov et al, 2016 ), thus confirming its specificity in neurons that were reprogrammed from fibroblasts from HD patients. The molecular target of EVP4593 is still unknown, but recent data showed that EVP4593 equally affected different SOC channels in HD iPSC-based GABAergic MSNs, suggesting that this compound could target SOCE regulatory proteins that are involved in both I CRAC and I SOC (e.g., STIM proteins) (Vigont et al, 2018 ). Huntington's disease iPSC-based GABAergic MSNs that were characterized by both excessive SOCE and progressive HD pathology (Nekrasov et al, 2016 ) were recently proposed to serve as a platform for personal drug screening in HD (Bezprozvanny and Kiselev, 2017 ; Vigont et al, 2018 ).…”

Store-Operated Calcium Channels in Physiological and Pathological States of the Nervous System

“…Additionally, knockdown of TRPC1, TRPC6, Orai1, or Orai2 also shows protective effects on medium spiny neuron spines in HD model mice (Wu J. et al, 2018). As such, SOCs have been studied as a potential therapeutic target for HD, with the effect of the potential anti-HD drug EVP4593 on calcium regulation via these channels being investigated in recent years (Wu et al, 2016;Vigont et al, 2018).…”