Alterations of Calcium Channels in a Mouse Model of Huntington’s Disease and Neuroprotection by Blockage of Ca<sub>V</sub>1 Channels

Miranda, Artur S.; Cardozo, Pablo Leal; Silva, Flávia Rodrigues da; Souza, Jéssica M. de; Olmo, Isabella G.; Cruz, Jáder Santos; Gomez, Marcus V.; Ribeiro, Fabíola M.; Vieira, Luciene Bruno

doi:10.1177/1759091419856811

Cited by 19 publications

(13 citation statements)

References 71 publications

(103 reference statements)

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“…They showed an important role for N-type VGCC in the increased release of synaptic vesicles at presynaptic terminals of HD cortical neurons in heterozygous zQ175 mice (Chen et al, 2018) and disease stage-dependent alterations in calcium influx in BACHD mice (Silva et al, 2017). A significant increase in L-type calcium currents in cortical neurons from BACHD mice has been also reported (Miranda et al, 2019). Here we have also shown greater calcium entry through VGCC in HD neurons.…”

Section: Discussionsupporting

confidence: 81%

STIM2 Mediates Excessive Store-Operated Calcium Entry in Patient-Specific iPSC-Derived Neurons Modeling a Juvenile Form of Huntington's Disease

Vigont

Grekhnev

Lebedeva

et al. 2021

Front. Cell Dev. Biol.

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Huntington's disease (HD) is a severe autosomal-dominant neurodegenerative disorder caused by a mutation within a gene, encoding huntingtin protein. Here we have used the induced pluripotent stem cell technology to produce patient-specific terminally differentiated GABA-ergic medium spiny neurons modeling a juvenile form of HD (HD76). We have shown that calcium signaling is dramatically disturbed in HD76 neurons, specifically demonstrating higher levels of store-operated and voltage-gated calcium uptakes. However, comparing the HD76 neurons with the previously described low-repeat HD models, we have demonstrated that the severity of calcium signaling alterations does not depend on the length of the polyglutamine tract of the mutant huntingtin. Here we have also observed greater expression of huntingtin and an activator of store-operated calcium channels STIM2 in HD76 neurons. Since shRNA-mediated suppression of STIM2 decreased store-operated calcium uptake, we have speculated that high expression of STIM2 underlies the excessive entry through store-operated calcium channels in HD pathology. Moreover, a previously described potential anti-HD drug EVP4593 has been found to attenuate high levels of both huntingtin and STIM2 that may contribute to its neuroprotective effect. Our results are fully supportive in favor of the crucial role of calcium signaling deregulation in the HD pathogenesis and indicate that the cornerstone of excessive calcium uptake in HD-specific neurons is a calcium sensor and store-operated calcium channels activator STIM2, which should become a molecular target for medical treatment and novel neuroprotective drug development.

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Section: Discussionsupporting

confidence: 81%

STIM2 Mediates Excessive Store-Operated Calcium Entry in Patient-Specific iPSC-Derived Neurons Modeling a Juvenile Form of Huntington's Disease

Vigont

Grekhnev

Lebedeva

et al. 2021

Front. Cell Dev. Biol.

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“…Neuropsychiatric disorders animal model [ 246 , 247 ]. Mouse model of Huntington's disease [ 248 ]. Cacna1c HET mice for depression-related behaviors [ 249 ].…”

Section: Resultsmentioning

confidence: 99%

Calcium channelopathies and intellectual disability: a systematic review

Kessi

Chen

Peng

et al. 2021

Orphanet J Rare Dis

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Background Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium channelopathies (CCs) and intellectual disability (ID)/global developmental delay (GDD) has been poorly investigated. We hypothesised that CCs play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD. As a result, we performed a systematic review to investigate the contribution of CCs, potential mechanisms underlying their involvement in ID/GDD, advancements in cell and animal models, treatments, brain anomalies in patients with CCs, and the existing gaps in the knowledge. We performed a systematic search in PubMed, Embase, ClinVar, OMIM, ClinGen, Gene Reviews, DECIPHER and LOVD databases to search for articles/records published before March 2021. The following search strategies were employed: ID and calcium channel, mental retardation and calcium channel, GDD and calcium channel, developmental delay and calcium channel. Main body A total of 59 reports describing 159 cases were found in PubMed, Embase, ClinVar, and LOVD databases. Variations in ten calcium channel genes including CACNA1A, CACNA1C, CACNA1I, CACNA1H, CACNA1D, CACNA2D1, CACNA2D2, CACNA1E, CACNA1F, and CACNA1G were found to be associated with ID/GDD. Most variants exhibited gain-of-function effect. Severe to profound ID/GDD was observed more for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. Furthermore, 157 copy number variations (CNVs) spanning calcium genes were identified in DECIPHER database. The leading genes included CACNA1C, CACNA1A, and CACNA1E. Overall, the underlying mechanisms included gain- and/ or loss-of-function, alteration in kinetics (activation, inactivation) and dominant-negative effects of truncated forms of alpha1 subunits. Forty of the identified cases featured cerebellar atrophy. We identified only a few cell and animal studies that focused on the mechanisms of ID/GDD in relation to CCs. There is a scarcity of studies on treatment options for ID/GDD both in vivo and in vitro. Conclusion Our results suggest that CCs play a major role in ID/GDD. While both gain- and loss-of-function variants are associated with ID/GDD, the mechanisms underlying their involvement need further scrutiny.

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“…In the YAC128 mouse model of HD, the L-VDCC antagonist nifedipine is mildly neuroprotective in vivo (Hong et al, 2015). A recent study performed a more complete analysis L-VDCCs in the BACHD mouse model of HD and found increases in Cav1.2 (but not Cav1.3) protein but not mRNA in the cortex, increases in cortical L-VDCC Ca 2+ currents in vitro, and neuroprotection by the L-VDCC antagonists isradipine and nifedipine on cortical neurons during glutamate toxicity in vitro (Miranda et al, 2019).…”

Section: Huntington's Diseasementioning

confidence: 99%

Targeting microglia L‐type voltage‐dependent calcium channels for the treatment of central nervous system disorders

Hopp

2020

J of Neuroscience Research

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Calcium (Ca2+) is a ubiquitous mediator of a multitude of cellular functions in the central nervous system (CNS). Intracellular Ca2+ is tightly regulated by cells, including entry via plasma membrane Ca2+ permeable channels. Of specific interest for this review are L‐type voltage‐dependent Ca2+ channels (L‐VDCCs), due to their pleiotropic role in several CNS disorders. Currently, there are numerous approved drugs that target L‐VDCCs, including dihydropyridines. These drugs are safe and effective for the treatment of humans with cardiovascular disease and may also confer neuroprotection. Here, we review the potential of L‐VDCCs as a target for the treatment of CNS disorders with a focus on microglia L‐VDCCs. Microglia, the resident immune cells of the brain, have attracted recent attention for their emerging inflammatory role in several CNS diseases. Intracellular Ca2+ regulates microglia transition from a resting quiescent state to an “activated” immune‐effector state and is thus a valuable target for manipulation of microglia phenotype. We will review the literature on L‐VDCC expression and function in the CNS and on microglia in vitro and in vivo and explore the therapeutic landscape of L‐VDCC‐targeting agents at present and future challenges in the context of Alzheimer's disease, Parkinson's disease, Huntington's disease, neuropsychiatric diseases, and other CNS disorders.

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Alterations of Calcium Channels in a Mouse Model of Huntington’s Disease and Neuroprotection by Blockage of Ca_V1 Channels

Cited by 19 publications

References 71 publications

STIM2 Mediates Excessive Store-Operated Calcium Entry in Patient-Specific iPSC-Derived Neurons Modeling a Juvenile Form of Huntington's Disease

STIM2 Mediates Excessive Store-Operated Calcium Entry in Patient-Specific iPSC-Derived Neurons Modeling a Juvenile Form of Huntington's Disease

Calcium channelopathies and intellectual disability: a systematic review

Targeting microglia L‐type voltage‐dependent calcium channels for the treatment of central nervous system disorders

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Alterations of Calcium Channels in a Mouse Model of Huntington’s Disease and Neuroprotection by Blockage of CaV1 Channels

Cited by 19 publications

References 71 publications

STIM2 Mediates Excessive Store-Operated Calcium Entry in Patient-Specific iPSC-Derived Neurons Modeling a Juvenile Form of Huntington's Disease

STIM2 Mediates Excessive Store-Operated Calcium Entry in Patient-Specific iPSC-Derived Neurons Modeling a Juvenile Form of Huntington's Disease

Calcium channelopathies and intellectual disability: a systematic review

Targeting microglia L‐type voltage‐dependent calcium channels for the treatment of central nervous system disorders

Contact Info

Product

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Alterations of Calcium Channels in a Mouse Model of Huntington’s Disease and Neuroprotection by Blockage of Ca_V1 Channels