Neuronal calcium sensor 1 (NCS1) dependent modulation of neuronal morphology and development

Abstract

Calcium (Ca 2+ ) signaling is critical for neuronal functioning and requires the concerted interplay of numerous Ca 2+ -binding proteins, including neuronal calcium sensor 1 (NCS1). Although an important role of NCS1 in neuronal processes and in neurodevelopmental and neurodegenerative diseases has been established, the underlying mechanisms remain enigmatic. Here, we systematically investigated the functions of NCS1 in the brain. Using Golgi-Cox staining, we observed a reduction in dendritic complexity and spine density in the prefrontal cortex and the dorsal hippocampus of Ncs1 −/− mice, which may underlie concomitantly observed deficits in memory acquisition. Subsequent RNA sequencing of Ncs1 −/− and Ncs1 +/+ mouse brain tissues revealed that NCS1 modulates gene expression related to neuronal morphology and development. Investigation of developmental databases further supported a molecular role of NCS1 during brain development by identifying temporal gene expression patterns. Collectively, this study provides insights into NCS1-dependent signaling and lays the foundation for a better understanding of NCS1-associated diseases.

A preliminary, prospective study of peripheral neuropathy and cognitive function in patients with breast cancer during taxane therapy

“…This study is the first report showing a decrease in NCS1 after taxane exposure in humans. The decrease in NCS1 levels over the course of taxane treatment in patients (Fig 4A ) follows the findings in pre-clinical models [14][15][16][17][18]. From these studies, alterations in intracellular calcium signaling is a likely critical pathway leading to calcium-related dysfunction occurring during chemotherapy.…”

“…NCS1 is a high affinity, low-capacity calcium binding protein which modulates calcium signaling inside cells. NCS1 is particularly important for key functions in neurons such as dendritic arborization [18]. Previous studies have shown that exposure to taxanes triggers proteolysis of NCS1 by calpain [13,14], a ubiquitous enzyme that is activated when calcium levels are increased.…”

“…We previously outlined a mechanism for paclitaxel-induced CIPN [13,14] and chemotherapy related cognitive impairment (CRCI) [15] and found agents that could prevent neuropathy in mouse models [15,16]. We found that paclitaxel binds to neuronal calcium sensor 1 (NCS1) [17] which is a key regulator of neuronal signaling [18], in part through binding to the inositol trisphosphate receptor (InsP3R) [13]. Briefly, when paclitaxel binds to NCS1 it enhances NCS1/InsP3Rdependent calcium release from the endoplasmic reticulum which leads to elevated PLOS ONE intracellular calcium.…”

NCS1 overexpression restored mitochondrial activity and behavioral alterations in a zebrafish model of Wolfram syndrome

“…NCS1 is a calcium sensor expressed predominantly in neurons that regulates many cellular functions, including neurotransmission, synaptic plasticity, exocytosis and endocytosis, neuronal growth, neuroprotection, and nuclear Ca 2+ regulation. Interestingly, NCS1 exerts similar functions as WFS1: both proteins regulate cytosolic Ca 2+ levels and IP3R-dependent ER-Ca 2+ release 20 , 32 , 33 , 34 modulate neuronal morphology and neurodevelopment, 49 , 50 mediate neuroprotection, 51 and have been implicated in neurodegenerative diseases and psychiatric disorders beyond WS. 52 , 53 , 54 In human fibroblasts, NCS1 knockdown impaired Ca 2+ homeostasis and mitochondrial function, demonstrating that NCS1 modulated [Ca 2+ ] m uptake and could be a target to maintain mitochondrial function and MAM integrity.…”

Fish Hydrolysate Supplementation Prevents Stress-Induced Dysregulation of Hippocampal Proteins Relative to Mitochondrial Metabolism and the Neuronal Network in Mice

“…Nesprin-1 (Syne 1) has been shown to play critical roles in neurogenesis and neuronal migration in mice [ 32 ]. Neuronal calcium sensor 1 (Ncs1) was reported to modulate neuronal morphology and development [ 33 ]. Glycogen synthase kinase-3 beta (Gsk3b) inhibition activates neurogenesis [ 34 ].…”