CRABP1-CaMKII-Agrn regulates the maintenance of neuromuscular junction in spinal motor neuron

Lin, Yu-Lung; Nhieu, Jennifer; Liu, Pei-Yao; Le, Gengyun; Lee, Jun Young; Wei, Chin-Wen; Lin, Yiwei; Oh, Sang-Hyun; Lowe, Dawn A.; Wei, Li‐Na

doi:10.1038/s41418-022-00959-4

Cited by 13 publications

(29 citation statements)

References 35 publications

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“…These novel activities of atRA were collectedly referred to as “non-canonical” and were later found to be mediated by the Cellular Retinoic Acid Binding Protein 1 (CRABP1) [ 22 ]. These CRABP1-mediated non-canonical activities of atRA were ultimately validated in careful studies of Crabp1 knockout (CKO) mice and cultures, which also revealed the physiological/disease relevance of CRABP1 [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ].…”

Section: Introduction: Canonical and Non-canonical Activities Of All-...mentioning

confidence: 90%

Section: Crabp1-signalsomesmentioning

confidence: 99%

“…A different CRABP1-signaling complex was identified from studying deteriorated heart function of CKO mice [ 26 , 27 ], and their premature weakening in motor function [ 33 ]. The expression study confirmed CRABP1 expression in cardiomyocytes [ 26 ] (relevant to the CKO heart phenotype) and motor neurons (relevant to the CKO motor function phenotype) [ 33 ]. This signaling complex is comprised of CRABP1 and calcium-calmodulin-dependent kinase 2 (CaMKII), an enzyme critical to calcium signaling/handling and highly enriched in both cardiomyocytes [ 69 ] and neurons [ 70 , 71 ].…”

Section: Crabp1-signalsomesmentioning

confidence: 99%

“…CRABP1 expression is tissue and cell-type specific. In the central nervous system, it is specifically and highly expressed in spinal cord MNs [ 33 ]. These neurons project to and innervate, primarily, muscles to form tightly regulated structures called neuromuscular junctions (NMJs) [ 79 ].…”

Section: Crabp1-signalsomesmentioning

confidence: 99%

“…MNs release neurotransmitters such as acetylcholine to induce muscle contraction, and express Agrin, a proteoglycan essential for NMJ development and maintenance [ 79 , 85 ]. Crabp1 is specifically expressed in the presynaptic compartment, comprised of MNs, but is not expressed in the post-synaptic muscle compartment [ 33 ]. This study identified CRABP1-CaMKII signaling in MNs, which contributed to the regulation of Agrin expression and its downstream target, the muscular LRP4-MuSK signaling that maintained AChR clusters and healthy NMJ [ 79 , 86 ].…”

Section: Crabp1-signalsomesmentioning

confidence: 99%

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CRABP1 in Non-Canonical Activities of Retinoic Acid in Health and Diseases

2022

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In this review, we discuss the emerging role of Cellular Retinoic Acid Binding Protein 1 (CRABP1) as a mediator of non-canonical activities of retinoic acid (RA) and relevance to human diseases. We first discuss the role of CRABP1 in regulating MAPK activities and its implication in stem cell proliferation, cancers, adipocyte health, and neuro-immune regulation. We then discuss an additional role of CRABP1 in regulating CaMKII activities, and its implication in heart and motor neuron diseases. Through molecular and genetic studies of Crabp1 knockout (CKO) mouse and culture models, it is established that CRABP1 forms complexes with specific signaling molecules to function as RA-regulated signalsomes in a cell context-dependent manner. Gene expression data and CRABP1 gene single nucleotide polymorphisms (SNPs) of human cancer, neurodegeneration, and immune disease patients implicate the potential association of abnormality in CRABP1 with human diseases. Finally, therapeutic strategies for managing certain human diseases by targeting CRABP1 are discussed.

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Section: Introduction: Canonical and Non-canonical Activities Of All-...mentioning

confidence: 90%

Section: Crabp1-signalsomesmentioning

confidence: 99%

Section: Crabp1-signalsomesmentioning

confidence: 99%

Section: Crabp1-signalsomesmentioning

confidence: 99%

Section: Crabp1-signalsomesmentioning

confidence: 99%

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CRABP1 in Non-Canonical Activities of Retinoic Acid in Health and Diseases

2022

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C21ORF2 mutations point towards primary cilia dysfunction in amyotrophic lateral sclerosis

De Decker,

Zelina,

Moens

et al. 2024

Brain

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Progressive loss of motor neurons is the hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS), but the underlying disease mechanisms remain incompletely understood. In this study, we investigate the effects of C21ORF2 mutations, a gene recently linked to ALS, and find that primary cilia are dysfunctional. Human patient-derived mutant C21ORF2 motor neurons have a reduced ciliary frequency and length. We report that C21ORF2 is located at the basal body of the primary cilium, and mutations associated with ALS alter this localization. Furthermore, we show that a reduction of C21ORF2 levels in cell lines and motor neurons is sufficient to cause fewer primary cilia and reduced cilial length. This ciliary dysfunction leads to defective downstream sonic hedgehog signalling and reduces the expression of cellular retinoic acid binding protein 1 (CRABP1), a protein involved in motor neuron maintenance and survival. In a compartmentalized co-culture system of motor neurons and muscle cells, these ciliary defects were associated with a reduced ability of neuromuscular junction formation. Interestingly, these cilia defects are seemingly not restricted to C21ORF2 ALS, as we also observed perturbed primary cilia in cultured motor neurons and post-mortem motor cortex from patients with the most common genetic subtype of ALS caused by repeat expansions in the C9ORF72 gene. Finally, overexpression of C21ORF2 in mutant C21ORF2 motor neurons rescued the ciliary frequency and length, CRAPBP1 expression and neuromuscular junction formation, confirming the importance of primary cilia for motor neuron function. These results point towards primary cilia dysfunction contributing to motor neuron degeneration in ALS and open new avenues for further research and interventions for this as yet untreatable disease.

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Interferon-γ Elicits Pathological Hallmarks of ALS in Human Motor Neurons

Chun

Lee

Bothwell

et al. 2022

Preprint

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Neuroinflammation is an established factor contributing to amyotrophic lateral sclerosis (ALS) pathology, implicating the possible detrimental effects of inflammatory cytokines to motor neurons. The RNA/DNA-binding protein TDP-43 has emerged as a pivotal actor in ALS, because TDP-43 mutations cause familial ALS and loss of nuclear TDP-43, associated with its redistribution into cytoplasmic aggregates (TDP-43 proteinopathy), in motor neurons occurs in 97% of ALS cases. However, mechanisms linking neuroinflammation to TDP-43 mis-localization have not been described. Programmed death-ligand 1 (PD-L1) is an immune-modulatory protein, highly expressed on cell surfaces following acute inflammatory stress. To determine which inflammatory cytokines might impact motor neuron function, seven cytokines known to be elevated in ALS patients cerebrospinal fluid were tested for their effects on PD-L1 expression in human iPSC-derived motor neurons. Among the tested cytokines, only interferon-gamma (IFN-gamma) was found to strongly promote PD-L1 expression. Thus, we hypothesized that excessive exposure to IFN-gamma may contribute to motor neuron degeneration in ALS. We observed that neuronal populations exposed to IFN-gamma exhibited severe TDP-43 cytoplasmic aggregation and excitotoxic behavior correlated with impaired neural firing activity, hallmarks of ALS pathology, in both normal and ALS mutant (TARDBPQ331K+/-) neurons. Single-cell RNA sequencing revealed possible mechanisms for these effects. Motor neurons exposed to IFN-gamma exhibited an extensive shift of their gene expression profile toward a neurodegenerative phenotype. Notably, IFN-gamma treatment induced aberrant expression levels for 70 genes that are listed in the recent literature as being dysregulated in ALS. Additionally, we found that genes related to neuronal electrophysiology, protein aggregation, and TDP-43 mis-regulation were abnormally expressed in IFN-gamma-treated cells. Moreover, IFN-gamma induced a significant reduction in the expression of genes that encode indispensable proteins for neuromuscular synapse development and maintenance, implying that cytokine exposure could directly impair signal transmission between motor axons and muscle membranes. Our findings suggest that IFN-gamma could be a potent upstream pathogenic driver of ALS and provide potential candidates for future therapeutic targets to treat sporadic forms of ALS, which account for roughly 90% of reported cases.

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CRABP1-CaMKII-Agrn regulates the maintenance of neuromuscular junction in spinal motor neuron

Cited by 13 publications

References 35 publications

CRABP1 in Non-Canonical Activities of Retinoic Acid in Health and Diseases

CRABP1 in Non-Canonical Activities of Retinoic Acid in Health and Diseases

C21ORF2 mutations point towards primary cilia dysfunction in amyotrophic lateral sclerosis

Interferon-γ Elicits Pathological Hallmarks of ALS in Human Motor Neurons

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