The Small-Molecule Flunarizine in Spinal Muscular Atrophy Patient Fibroblasts Impacts on the Gemin Components of the SMN Complex and TDP43, an RNA-Binding Protein Relevant to Motor Neuron Diseases

Sapaly, Delphine; Delers, Perrine; Coridon, Jennifer; Salman, Badih; Letourneur, Franck; Dumont, Florent; Lefebvre, Suzie

doi:10.3389/fmolb.2020.00055

Cited by 4 publications

(3 citation statements)

References 101 publications

(131 reference statements)

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“…No drug effects were observed on CaMKII protein levels or phosphorylation, ruling out a possible involvement of CaMKII, which also regulates the AChR expression and clustering 54 , 55 . SMN and Unrip (another SMN-complex component) protein levels were unchanged, as expected 56 . Thus, flunarizine may promote agrin signalling since Lrp4/MuSK, β1 integrins and α-dystroglycan are all agrin receptors involved in NMJ biology 25 .…”

Section: Resultssupporting

confidence: 70%

“…Oxidative damages might also contribute to NMJ alterations in motoneuron diseases 68 . Flunarizine reduces the pro-oxydant TXNIP in SMA patient fibroblasts 56 like other calcium channel blockers do in pancreatic beta cells 69 . Interestingly, Txnip transcripts were upregulated in muscles with no satellite cells (SC) compared with SC replete muscles 70 that is reminiscent of reduced SC number in muscles of SMA mice [71][72][73] .…”

Section: Flunarizine Reduces Txnip Expression In Skeletal Muscles Of ...mentioning

confidence: 95%

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A link between agrin signalling and Cav3.2 at the neuromuscular junction in spinal muscular atrophy

Delers

Sapaly

Salman

et al. 2022

Sci Rep

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SMN protein deficiency causes motoneuron disease spinal muscular atrophy (SMA). SMN-based therapies improve patient motor symptoms to variable degrees. An early hallmark of SMA is the perturbation of the neuromuscular junction (NMJ), a synapse between a motoneuron and muscle cell. NMJ formation depends on acetylcholine receptor (AChR) clustering triggered by agrin and its co-receptors lipoprotein receptor-related protein 4 (LRP4) and transmembrane muscle-specific kinase (MuSK) signalling pathway. We have previously shown that flunarizine improves NMJs in SMA model mice, but the mechanisms remain elusive. We show here that flunarizine promotes AChR clustering in cell-autonomous, dose- and agrin-dependent manners in C2C12 myotubes. This is associated with an increase in protein levels of LRP4, integrin-beta-1 and alpha-dystroglycan, three agrin co-receptors. Furthermore, flunarizine enhances MuSK interaction with integrin-beta-1 and phosphotyrosines. Moreover, the drug acts on the expression and splicing of Agrn and Cacna1h genes in a muscle-specific manner. We reveal that the Cacna1h encoded protein Cav3.2 closely associates in vitro with the agrin co-receptor LRP4. In vivo, it is enriched nearby NMJs during neonatal development and the drug increases this immunolabelling in SMA muscles. Thus, flunarizine modulates key players of the NMJ and identifies Cav3.2 as a new protein involved in the NMJ biology.

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Section: Resultssupporting

confidence: 70%

Section: Flunarizine Reduces Txnip Expression In Skeletal Muscles Of ...mentioning

confidence: 95%

A link between agrin signalling and Cav3.2 at the neuromuscular junction in spinal muscular atrophy

Delers

Sapaly

Salman

et al. 2022

Sci Rep

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“…The mode of action resides in an increase in abundance of a subset of components of the SMN-Gemins complex, Gemins2, 3, and 4. Flunarizine exposure also decreases the expression of thioredoxin-interacting protein TXNIP, which is a pro-oxidant encoded by an mRNA that is targeted by Gemin5 [45].…”

Section: Therapies In Pre-clinical Developmentmentioning

confidence: 99%

Therapeutic interventions for spinal muscular atrophy: preclinical and early clinical development opportunities

Servais

Baranello

Scoto

et al. 2021

Expert Opinion on Investigational Drugs

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Introduction: Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative neuromuscular disease that presents primarily in children. Abnormalities in the SMN1 gene cause reduced levels of the survival motor neuron (SMN) protein, while a second gene, SMN2, produces low levels of functional SMN protein. Currently available drugs do not cure, so a significant unmet need remains for patients treated after symptom onset. Areas covered: Drugs available in the clinic, investigational agents and key questions for researchers are discussed. A pragmatic search of the literature was performed to identify therapies in late stages of preclinical, or in early stages of clinical development. This list was compared to the CureSMA pipeline for completeness. Drugs approved for indications that have potential for impact for SMA were included. These drugs target the primary deficiency in SMN protein or other pathways involved in SMA pathophysiology that are not SMN-protein dependent. Expert opinion: Children treated after the onset of symptoms continue to have significant disability. Given the heterogeneity of the population phenotype evidenced by variable response to initial therapy, age at treatment onset and the need to demonstrate added value beyond approved therapeutics, the clinical development of new drugs will be challenging.

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SMN regulates GEMIN5 expression and acts as a modifier of GEMIN5-mediated neurodegeneration

et al. 2023

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The Small-Molecule Flunarizine in Spinal Muscular Atrophy Patient Fibroblasts Impacts on the Gemin Components of the SMN Complex and TDP43, an RNA-Binding Protein Relevant to Motor Neuron Diseases

Cited by 4 publications

References 101 publications

A link between agrin signalling and Cav3.2 at the neuromuscular junction in spinal muscular atrophy

A link between agrin signalling and Cav3.2 at the neuromuscular junction in spinal muscular atrophy

Therapeutic interventions for spinal muscular atrophy: preclinical and early clinical development opportunities

SMN regulates GEMIN5 expression and acts as a modifier of GEMIN5-mediated neurodegeneration

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