A spinal muscular atrophy modifier implicates the SMN protein in SNARE complex assembly at neuromuscular synapses

Kim, Jeong-Ki; Jha, Narendra Nath; Awano, Tomoyuki; Caine, Charlotte; Gollapalli, Kishore; Welby, Emily; Kim, Seung-Soo; Fuentes-Moliz, Andrea; Wang, Xueyong; Feng, Zhichun; Sera, Fusako; Takeda, Taishi; Homma, Shunichi; Ko, Chien‐Ping; Tabares, Lucı́a; Ebert, Allison D.; Rich, Mark M.; Monani, Umrao R.

doi:10.1016/j.neuron.2023.02.004

Cited by 16 publications

(15 citation statements)

References 71 publications

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“…Thus, the amplitude ratio between the second and the first EPP (pair-pulse facilitation) was reduced in the presence of nifedipine, indicating that the probability of release was already high during the first shock, in agreement with the high rate of spontaneous events during low-frequency stimulation. The lack of a net effect of nifedipine on the RRP is consistent with, among others, the reduction in docked vesicles [16], active zones [18], synaptotagmin 2 [19], and SNARE complexes [39] in SMA motor nerve terminals. Thus, the present data may reflect the upper functional limit during high electrical stimulation.…”

Section: Nifedipine Increases the Rrp Size In Controls But Not In Sma...supporting

confidence: 86%

Nifedipine Ameliorates Cellular Differentiation Defects of Smn-Deficient Motor Neurons and Enhances Neuromuscular Transmission in SMA Mice

Tejero

Alsakkal

Hennlein

et al. 2023

IJMS

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In spinal muscular atrophy (SMA), mutations in or loss of the Survival Motor Neuron 1 (SMN1) gene reduce full-length SMN protein levels, which leads to the degeneration of a percentage of motor neurons. In mouse models of SMA, the development and maintenance of spinal motor neurons and the neuromuscular junction (NMJ) function are altered. Since nifedipine is known to be neuroprotective and increases neurotransmission in nerve terminals, we investigated its effects on cultured spinal cord motor neurons and motor nerve terminals of control and SMA mice. We found that application of nifedipine increased the frequency of spontaneous Ca2+ transients, growth cone size, cluster-like formations of Cav2.2 channels, and it normalized axon extension in SMA neurons in culture. At the NMJ, nifedipine significantly increased evoked and spontaneous release at low-frequency stimulation in both genotypes. High-strength stimulation revealed that nifedipine increased the size of the readily releasable pool (RRP) of vesicles in control but not SMA mice. These findings provide experimental evidence about the ability of nifedipine to prevent the appearance of developmental defects in SMA embryonic motor neurons in culture and reveal to which extent nifedipine could still increase neurotransmission at the NMJ in SMA mice under different functional demands.

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Section: Nifedipine Increases the Rrp Size In Controls But Not In Sma...supporting

confidence: 86%

Nifedipine Ameliorates Cellular Differentiation Defects of Smn-Deficient Motor Neurons and Enhances Neuromuscular Transmission in SMA Mice

Tejero

Alsakkal

Hennlein

et al. 2023

IJMS

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“…Moreover, wild-type mouse motor neurons cultured with bafilomycin A1 in the presence of neurotrophic factors displayed increased LC3-II and reduced Smn levels relative to untreated controls, suggesting that inhibitors of autophagic flux resulted in reduced Smn protein levels in healthy controls ( Periyakaruppiah et al, 2016 ). In line with these findings, SMA patient fibroblasts treated with lysosomal inhibitors displayed an accumulation of p62, while LC3-II increase was significantly lower than the increase observed in control fibroblasts, suggesting that autophagosome formation was not impaired ( Rodriguez-Muela et al, 2018 ) A potential mechanism that could underlie the autophagic flux defects observed in SMA may be due to the disrupted SNARE complex assembly, an observation that has recently been described following SMN depletion ( Kim et al, 2023 ). Fundamentally, the SNARE complex is required for autophagosome-lysosome fusion and therefore, when impaired, autophagic flux is expected to be reduced ( Mohamud et al, 2018 ).…”

Section: Autophagy Dysregulation In Smasupporting

confidence: 70%

Autophagy in spinal muscular atrophy: from pathogenic mechanisms to therapeutic approaches

Rashid,

Dimitriadi

2024

Front. Cell. Neurosci.

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Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by the depletion of the ubiquitously expressed survival motor neuron (SMN) protein. While the genetic cause of SMA has been well documented, the exact mechanism(s) by which SMN depletion results in disease progression remain elusive. A wide body of evidence has highlighted the involvement and dysregulation of autophagy in SMA. Autophagy is a highly conserved lysosomal degradation process which is necessary for cellular homeostasis; defects in the autophagic machinery have been linked with a wide range of neurodegenerative disorders, including amyotrophic lateral sclerosis, Alzheimer’s disease and Parkinson’s disease. The pathway is particularly known to prevent neurodegeneration and has been suggested to act as a neuroprotective factor, thus presenting an attractive target for novel therapies for SMA patients. In this review, (a) we provide for the first time a comprehensive summary of the perturbations in the autophagic networks that characterize SMA development, (b) highlight the autophagic regulators which may play a key role in SMA pathogenesis and (c) propose decreased autophagic flux as the causative agent underlying the autophagic dysregulation observed in these patients.

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“…The hippo signaling pathway plays a critical role in tissue growth and regeneration [ 36 - 38 ], whereas nucleotide excision repair is involved in DNA damage repair [ 39 , 40 ]. SNARE interactions in vesicular transport are related to synaptic transmission and neurodegenerative diseases [ 41 - 43 ], whereas the NF-kappa B signaling pathway is associated with inflammation and immune responses [ 44 , 45 ]. However, the specific roles of these pathways in LFH warrant further investigation.…”

Section: Discussionmentioning

confidence: 99%

Exploring lncRNA Expression Patterns in Patients With Hypertrophied Ligamentum Flavum

Chen,

Zhong,

Qiu

et al. 2024

Neurospine

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Objective: Hypertrophy ligamentum flavum (LFH) is a common cause of lumbar spinal stenosis, resulting in significant disability and morbidity. Although long noncoding RNAs (lncRNAs) have been associated with various biological processes and disorders, their involvement in LFH remains not fully understood.Methods: Human ligamentum flavum samples were analyzed using lncRNA sequencing followed by validation through quantitative real-time polymerase chain reaction. To explore the potential biological functions of differentially expressed lncRNA-associated genes, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. We also studied the impact of lncRNA PARD3-AS1 on the progression of LFH <i>in vitro</i>.Results: In the LFH tissues when compared to that in the nonhypertrophic ligamentum flavum (LFN) tissues, a total of 1,091 lncRNAs exhibited differential expression, with 645 upregulated and 446 downregulated. Based on GO analysis, the differentially expressed transcripts primarily participated in metabolic processes, organelles, nuclear lumen, cytoplasm, protein binding, nucleic acid binding, and transcription factor activity. Moreover, KEGG pathway analysis indicated that the differentially expressed lncRNAs were associated with the hippo signaling pathway, nucleotide excision repair, and nuclear factor-kappa B signaling pathway. The expression of PARD3-AS1, RP11-430G17.3, RP1-193H18.3, and H19 was confirmed to be consistent with the sequencing analysis. Inhibition of PARD3-AS1 resulted in the suppression of fibrosis in LFH cells, whereas the overexpression of PARD3-AS1 promoted fibrosis in LFH cells <i>in vitro</i>.Conclusion: This study identified distinct expression patterns of lncRNAs that are linked to LFH, providing insights into its underlying mechanisms and potential prognostic and therapeutic interventions. Notably, PARD3-AS1 appears to play a significant role in the pathophysiology of LFH.

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A spinal muscular atrophy modifier implicates the SMN protein in SNARE complex assembly at neuromuscular synapses

Cited by 16 publications

References 71 publications

Nifedipine Ameliorates Cellular Differentiation Defects of Smn-Deficient Motor Neurons and Enhances Neuromuscular Transmission in SMA Mice

Nifedipine Ameliorates Cellular Differentiation Defects of Smn-Deficient Motor Neurons and Enhances Neuromuscular Transmission in SMA Mice

Autophagy in spinal muscular atrophy: from pathogenic mechanisms to therapeutic approaches

Exploring lncRNA Expression Patterns in Patients With Hypertrophied Ligamentum Flavum

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