A role for complexes of survival of motor neurons (SMN) protein with gemins and profilin in neurite-like cytoplasmic extensions of cultured nerve cells

Sharma, Aarti; Lambrechts, Anja; Liang, Hao; Le, Thanh Van; Sewry, Caroline A.; Ampè, Christophe; Burghes, Arthur H.M.; Morris, Glenn E.

doi:10.1016/j.yexcr.2005.05.014

Cited by 124 publications

(123 citation statements)

References 55 publications

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“…62,63 This latter view is supported by studies showing that the SMN protein is present in transport granules of cultured motoneurons travelling down the axon. 64,65 Some of SMN's interaction partners such as hnRNP R and Q, 66 profilins (proteins associated with microfilaments) 65,67 or the Fragile X Mental Retardation protein FMRP 68 support such a peripheral function. Thus it has been proposed that SMN could be involved in the transport or translational regulation of actin mRNA or other so far not characterized mRNAs and thereby control the organisation of the axon terminal.…”

Section: The Architecture Of Smn Genes With Regard To Exon 7 Definitionmentioning

confidence: 99%

“…Thus it has been proposed that SMN could be involved in the transport or translational regulation of actin mRNA or other so far not characterized mRNAs and thereby control the organisation of the axon terminal. 62,65 Interestingly, the phenotypes observed in SMA mouse models all show first perturbations of the neuromuscular junctions, before an actual cell death can be confirmed in the spinal cord. [69][70][71][72][73][74][75][76] This strongly favours a dying mouse Smn and expressing human SMN2.…”

Section: The Architecture Of Smn Genes With Regard To Exon 7 Definitionmentioning

confidence: 99%

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Repair of pre-mRNA splicing

2010

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Section: The Architecture Of Smn Genes With Regard To Exon 7 Definitionmentioning

confidence: 99%

Section: The Architecture Of Smn Genes With Regard To Exon 7 Definitionmentioning

confidence: 99%

Repair of pre-mRNA splicing

2010

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Section: Smn: How Many Functions Can a Single Protein Possess?mentioning

confidence: 99%

“…However, because SMN is part of a very large multimeric complex, it is possible that SMND7 is stabilized in vivo due to its association with other proteins in the complex [Burghes and Beattie, 2009]. In favor of this hypothesis is the observation that expression of the SMND7 isoform in a Smn À/À ; SMN2 þ/þ background dramatically improves the survival of a severe mouse model of the disease [Le et al, 2005].The SMN complex is comprised of several proteins (many still unidentified), including Gemin2-8 and UNRIP (UNR-interacting protein, or STRAP) [Charroux et al, 1999;Charroux et al, 2000;Baccon et al, 2002;Gubitz et al, 2002;Pellizzoni et al, 2002;Carissimi et al, 2006]. The best characterized function of the complex is in the assembly of small nuclear ribonucleoproteins (snRNPs), which are involved in several aspects of RNA metabolism [see Workman et al, 2012 for a review].…”

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confidence: 99%

“…Hints regarding neuronal-and muscle-specific SMN functions were recognized through the identification of interacting proteins in the SMN-complex. These can be divided into two groups: proteins associated with cytoskeletal dynamics and mRNA binding proteins (mRBPs) involved in the regulation of translation, transport, stabilization and localization of mRNAs [Giesemann et al, 1999;Sharma et al, 2005;Bowerman et al, 2007;Wen et al, 2010]. In keeping with these findings, SMN protein deficiency could lead to the disruption of axonal transport and localization of several mRNAs, and/or of the assembly of specific snRNPs involved in transport and translation of a subset of axonal mRNAs: these defects would be responsible for the pathogenesis of SMA [see Fallini et al, 2012 for a review].…”

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Solving the puzzle of spinal muscular atrophy: What are the missing pieces?

Tiziano

Melki

Simard

2013

American J of Med Genetics Pt A

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Spinal muscular atrophy (SMA) is an autosomal recessive, lower motor neuron disease. Clinical heterogeneity is pervasive: three infantile (type I-III) and one adult-onset (type IV) forms are recognized. Type I SMA is the most common genetic cause of death in infancy and accounts for about 50% of all patients with SMA. Most forms of SMA are caused by mutations of the survival motor neuron (SMN1) gene. A second gene that is 99% identical to SMN1 (SMN2) is located in the same region. The only functionally relevant difference between the two genes identified to date is a C ! T transition in exon 7 of SMN2, which determines an alternative spliced isoform that predominantly excludes exon 7. Thus, SMN2 genes do not produce sufficient full length SMN protein to prevent the onset of the disease. Since the identification of the causative mutation, biomedical research of SMA has progressed by leaps and bounds: from clues on the function of SMN protein, to the development of different models of the disease, to the identification of potential treatments, some of which are currently in human trials. The aim of this review is to elucidate the current state of knowledge, emphasizing how close we are to the solution of the puzzle that is SMA, and, more importantly, to highlight the missing pieces of this puzzle. Filling in these gaps in our knowledge will likely accelerate the development and delivery of efficient treatments for SMA patients and be a prerequisite towards achieving our final goal, the cure of SMA. Ó 2013 Wiley Periodicals, Inc. Key words: spinal muscular atrophy; SMN INTRODUCTIONSpinal muscular atrophy (SMA) is a lower motor neuron disease that predominantly affects spinal cord anterior horn cells and brain stem nuclei [Dubowitz, 1995; reviewed in Hamilton and Gillingwater, 2013]. Alpha-motor neuron cell degeneration results in progressive, symmetrical skeletal muscle atrophy of limbs and trunk, spreading proximal to distal [Crawford and Pardo, 1996]. Clinical heterogeneity is pervasive: based on the age of onset and on the maximum motor achievement of patients, three infantile (type I-III) and one adult-onset (type IV) forms are commonly recognized. Classification criteria are summarized in Table I. However, this rigid classification does not accurately depict the range of SMA clinical phenotypes, which display a more continuous spectrum, ranging from prenatal onset to almost asymptomatic patients. SMA is a common autosomal recessive disorder (incidence is $1 in 6,000 in most ethnicities). Type I SMA is the most common genetic cause of death in infancy and accounts for about 50% of all patients with SMA [Crawford and Pardo, 1996;Prior, 2010].Most forms of SMA are caused by mutations in the survival motor neuron (SMN) gene, which was isolated in 1995 in chromosome 5q13 harboring a segmental duplication [Lefebvre et al., 1995]. Mutations in SMN1 are responsible for the four forms of SMA [Wirth, 2000;Alías et al., 2009]. A second gene that is 99% identical to SMN1, the SMN2 gene, is located in the same region [Le...

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Whole‐blood dysregulation of actin‐cytoskeleton pathway in adult spinal muscular atrophy patients

Siranosian

Nery

Alves

et al. 2020

Ann Clin Transl Neurol

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Objective: Recent advances in therapeutics have improved prognosis for severely affected spinal muscular atrophy (SMA) type 1 and 2 patients, while the best method of treatment for SMA type 3 patients with later onset of disease is unknown. To better characterize the SMA type 3 population and provide potential therapeutic targets, we aimed to understand gene expression differences in whole blood of SMA type 3 patients (n = 31) and age-and gendermatched controls (n = 34). Methods: We performed the first large-scale whole blood transcriptomic screen with L1000, a rapid, high-throughput gene expression profiling technology that uses 978 landmark genes to capture a representation of the transcriptome and predict expression of 9196 additional genes. Results: The primary downregulated KEGG pathway in adult SMA type 3 patients was "Regulation of Actin Cytoskeleton," and downregulated expression of key genes in this pathway, including ROCK1, RHOA, and ACTB, was confirmed in the same whole blood samples using RT-qPCR. SMA type 3 patientderived fibroblasts had lower expression of these genes compared to control fibroblasts from unaffected first-degree relatives. Overexpression of SMN levels using an AAV vector in fibroblasts did not normalize ROCK1, RHOA, and ACTB mRNA expression, indicating the involvement of additional genes in cytoskeleton dynamic regulation. Interpretation: Our findings from whole blood and patient-derived fibroblasts suggest SMA type 3 patients have decreased expression of actin cytoskeleton regulators. These observations provide new insights and potential therapeutic targets for SMA patients with longstanding denervation and secondary musculoskeletal pathophysiology.

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A role for complexes of survival of motor neurons (SMN) protein with gemins and profilin in neurite-like cytoplasmic extensions of cultured nerve cells

Cited by 124 publications

References 55 publications

Repair of pre-mRNA splicing

Repair of pre-mRNA splicing

Solving the puzzle of spinal muscular atrophy: What are the missing pieces?

Whole‐blood dysregulation of actin‐cytoskeleton pathway in adult spinal muscular atrophy patients

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