scholarly journals A subset of SMN complex members have a specific role in tissue regeneration via ERBB pathway-mediated proliferation

2019 ◽  
Author(s):  
Wuhong Pei ◽  
Lisha Xu ◽  
Zelin Chen ◽  
Claire C Slevin ◽  
Kade P Pettie ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Tissue Regeneration ◽  
Hair Cells ◽  
Muscular Atrophy ◽  
Essential Gene ◽  
Genetic Diseases ◽  
Rna Seq ◽  
Genetic Pathways ◽  
Smn Complex ◽  
Survival Of Motor Neurons

AbstractSpinal Muscular Atrophy (SMA) is the most common genetic disease in childhood. SMA is generally caused by mutations in SMN1. The Survival of Motor Neurons (SMN) complex consists of SMN1, Gemins (2–8) and Strap/Unrip. We previously demonstrated smn1 and gemin5 inhibited tissue regeneration in zebrafish. Here we investigated each individual SMN complex member and identified gemin3 as another regeneration-essential gene. These three genes are likely pan-regenerative since they affect the regeneration of hair cells, liver and caudal fin. RNA-Seq and miRNA-Seq analyses reveal that smn1, gemin3, and gemin5 are linked to a common set of genetic pathways, including the tp53 and ErbB pathways. Additional studies indicated all three genes facilitate regeneration by inhibiting the ErbB pathway, thereby allowing cell proliferation in the injured neuromasts. This study provides a new understanding of the SMN complex and a potential etiology for SMA and potentially other rare unidentified genetic diseases with similar symptoms.

scholarly journals The Survival of Motor Neurons Protein Determines the Capacity for snRNP Assembly: Biochemical Deficiency in Spinal Muscular Atrophy

2005 ◽  
Vol 25 (13) ◽  
pp. 5543-5551 ◽  
Author(s):  
Lili Wan ◽  
Daniel J. Battle ◽  
Jeongsik Yong ◽  
Amelie K. Gubitz ◽  
Stephen J. Kolb ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Protein Levels ◽  
Small Nuclear Ribonucleoprotein ◽  
Cell Extracts ◽  
Smn Complex ◽  
Survival Of Motor Neurons ◽  
Smn Protein ◽  
Nuclear Ribonucleoprotein

ABSTRACT Reduction of the survival of motor neurons (SMN) protein levels causes the motor neuron degenerative disease spinal muscular atrophy, the severity of which correlates with the extent of reduction in SMN. SMN, together with Gemins 2 to 7, forms a complex that functions in the assembly of small nuclear ribonucleoprotein particles (snRNPs). Complete depletion of the SMN complex from cell extracts abolishes snRNP assembly, the formation of heptameric Sm cores on snRNAs. However, what effect, if any, reduction of SMN protein levels, as occurs in spinal muscular atrophy patients, has on the capacity of cells to produce snRNPs is not known. To address this, we developed a sensitive and quantitative assay for snRNP assembly, the formation of high-salt- and heparin-resistant stable Sm cores, that is strictly dependent on the SMN complex. We show that the extent of Sm core assembly is directly proportional to the amount of SMN protein in cell extracts. Consistent with this, pulse-labeling experiments demonstrate a significant reduction in the rate of snRNP biogenesis in low-SMN cells. Furthermore, extracts of cells from spinal muscular atrophy patients have a lower capacity for snRNP assembly that corresponds directly to the reduced amount of SMN. Thus, SMN determines the capacity for snRNP biogenesis, and our findings provide evidence for a measurable deficiency in a biochemical activity in cells from patients with spinal muscular atrophy.

SMN complexes of nucleus and cytoplasm: A proteomic study for SMA therapy

2010 ◽  
Vol 1 (4) ◽  
Author(s):  
Heidi Fuller ◽  
Glenn Morris
Keyword(s):  
Motor Neurons ◽  
Muscular Atrophy ◽  
Ubiquitin Proteasome System ◽  
Neuromuscular Disorder ◽  
Nuclear Extracts ◽  
Smn Complex ◽  
Proteomic Study ◽  
Ubiquitin Proteasome ◽  
Survival Of Motor Neurons ◽  
Smn Protein

AbstractReduced levels of the survival of motor neurons protein (SMN), cause the inherited neuromuscular disorder, spinal muscular atrophy (SMA). The majority of therapeutic approaches to date have been focused on finding ways to increase expression of functional SMN protein, though stabilization of SMN protein may also be an important consideration. SMN interacts, directly or indirectly, stably or transiently, with a large number of other proteins, some of which contribute to SMN stability and may therefore be potential targets for SMA therapy. We recently characterized the nuclear SMN interactome using LC-MALDI-TOF/TOF analysis of anti-SMN pull-downs and identified myb-binding protein-1a (Mybbp1a) as a novel partner. In light of interest in cytoplasm-specific roles of the SMN complex, we have applied the same approach to characterise the cytoplasmic SMN interactome. We now show that SMN complexes from HeLa cytoplasmic extracts differ significantly from those found in nuclear extracts, with gemin5, importinbeta and annexin A2 easily detected only in the cytoplasmic extracts, whereas interaction of SMN with Mybbp1a appears to occur only in the nucleus. SMN is ubiquitinylated and we also found proteins of the ubiquitin-proteasome system associated with SMN in the cytoplasm.

scholarly journals SMN-independent Subunits of the SMN Complex

2007 ◽  
Vol 282 (38) ◽  
pp. 27953-27959 ◽  
Author(s):  
Daniel J. Battle ◽  
Mumtaz Kasim ◽  
Jin Wang ◽  
Gideon Dreyfuss
Keyword(s):  
Motor Neurons ◽  
Atp Hydrolysis ◽  
Muscular Atrophy ◽  
Small Nuclear Rna ◽  
Small Nuclear Ribonucleoprotein ◽  
Cell Extracts ◽  
Smn Complex ◽  
Small Nuclear Rnas ◽  
Survival Of Motor Neurons ◽  
Nuclear Ribonucleoprotein

The survival of motor neurons (SMN) complex is essential for the biogenesis of small nuclear ribonucleoprotein (snRNP) complexes in eukaryotic cells. Reduced levels of SMN cause the motor neuron degenerative disease, spinal muscular atrophy. We identify here stable subunits of the SMN complex that do not contain SMN. Sedimentation and immunoprecipitation experiments using cell extracts reveal at least three complexes composed of Gemin3, -4, and -5; Gemin6, -7, and unrip; and SMN with Gemin2, as well as free Gemin5. Complexes containing Gemin3-Gemin4-Gemin5 and Gemin6-Gemin7-unrip persist at similar levels when SMN is reduced. In cells, immunofluorescence microscopy shows differential localization of Gemin5 after cell stress. We further show that the Gemin5-containing subunits bind small nuclear RNA independently of the SMN complex and without a requirement for exogenous ATP. ATP hydrolysis is, however, required for displacement of small nuclear RNAs from the Gemin5-containing subunits and their assembly into snRNPs. These findings demonstrate a modular nature of the SMN complex and identify a new intermediate in the snRNP assembly process.

scholarly journals The SMN Complex Is Associated with snRNPs throughout Their Cytoplasmic Assembly Pathway

2002 ◽  
Vol 22 (18) ◽  
pp. 6533-6541 ◽  
Author(s):  
Séverine Massenet ◽  
Livio Pellizzoni ◽  
Sergey Paushkin ◽  
Iain W. Mattaj ◽  
Gideon Dreyfuss
Keyword(s):  
Motor Neurons ◽  
Muscular Atrophy ◽  
Sm Proteins ◽  
Assembly Pathway ◽  
Smn Complex ◽  
Complex Functions ◽  
Survival Of Motor Neurons ◽  
The Common ◽  
Smn Protein ◽  
Cytoplasmic Assembly

ABSTRACT The common neurodegenerative disease spinal muscular atrophy is caused by reduced levels of the survival of motor neurons (SMN) protein. SMN associates with several proteins (Gemin2 to Gemin6) to form a large complex which is found both in the cytoplasm and in the nucleus. The SMN complex functions in the assembly and metabolism of several RNPs, including spliceosomal snRNPs. The snRNP core assembly takes place in the cytoplasm from Sm proteins and newly exported snRNAs. Here, we identify three distinct cytoplasmic SMN complexes, each representing a defined intermediate in the snRNP biogenesis pathway. We show that the SMN complex associates with newly exported snRNAs containing the nonphosphorylated form of the snRNA export factor PHAX. The second SMN complex identified contains assembled Sm cores and m3G-capped snRNAs. Finally, the SMN complex is associated with a preimport complex containing m3G-capped snRNP cores bound to the snRNP nuclear import mediator snurportin1. Thus, the SMN complex is associated with snRNPs during the entire process of their biogenesis in the cytoplasm and may have multiple functions throughout this process.

scholarly journals Gemin3

1999 ◽  
Vol 147 (6) ◽  
pp. 1181-1194 ◽  
Author(s):  
Bernard Charroux ◽  
Livio Pellizzoni ◽  
Robert A. Perkinson ◽  
Andrej Shevchenko ◽  
Matthias Mann ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Muscular Atrophy ◽  
Critical Role ◽  
Interacting Protein ◽  
Dead Box ◽  
Core Proteins ◽  
Smn Complex ◽  
Survival Of Motor Neurons ◽  
Smn Gene ◽  
Smn Protein

The survival of motor neurons (SMN) gene is the disease gene of spinal muscular atrophy (SMA), a common motor neuron degenerative disease. The SMN protein is part of a complex containing several proteins, of which one, SIP1 (SMN interacting protein 1), has been characterized so far. The SMN complex is found in both the cytoplasm and in the nucleus, where it is concentrated in bodies called gems. In the cytoplasm, SMN and SIP1 interact with the Sm core proteins of spliceosomal small nuclear ribonucleoproteins (snRNPs), and they play a critical role in snRNP assembly. In the nucleus, SMN is required for pre-mRNA splicing, likely by serving in the regeneration of snRNPs. Here, we report the identification of another component of the SMN complex, a novel DEAD box putative RNA helicase, named Gemin3. Gemin3 interacts directly with SMN, as well as with SmB, SmD2, and SmD3. Immunolocalization studies using mAbs to Gemin3 show that it colocalizes with SMN in gems. Gemin3 binds SMN via its unique COOH-terminal domain, and SMN mutations found in some SMA patients strongly reduce this interaction. The presence of a DEAD box motif in Gemin3 suggests that it may provide the catalytic activity that plays a critical role in the function of the SMN complex on RNPs.

scholarly journals Genome-wide RNA-Seq of Human Motor Neurons Implicates Selective ER Stress Activation in Spinal Muscular Atrophy

2015 ◽  
Vol 17 (5) ◽  
pp. 569-584 ◽  
Author(s):  
Shi-Yan Ng ◽  
Boon Seng Soh ◽  
Natalia Rodriguez-Muela ◽  
David G. Hendrickson ◽  
Feodor Price ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Er Stress ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Rna Seq ◽  
Genome Wide ◽  
Human Motor ◽  
Stress Activation

scholarly journals Key role of SMN/SYNCRIP and RNA-Motif 7 in spinal muscular atrophy: RNA-Seq and motif analysis of human motor neurons

Brain ◽  
2019 ◽  
Vol 142 (2) ◽  
pp. 276-294 ◽  
Author(s):  
Federica Rizzo ◽  
Monica Nizzardo ◽  
Shikha Vashisht ◽  
Erika Molteni ◽  
Valentina Melzi ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Rna Seq ◽  
Motif Analysis ◽  
Human Motor ◽  
Rna Motif

scholarly journals Lymphotropic Herpesvirus saimiri Uses the SMN Complex To Assemble Sm Cores on Its Small RNAs

2005 ◽  
Vol 25 (2) ◽  
pp. 602-611 ◽  
Author(s):  
Tracey J. Golembe ◽  
Jeongsik Yong ◽  
Daniel J. Battle ◽  
Wenqin Feng ◽  
Lili Wan ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Small Rnas ◽  
Herpesvirus Saimiri ◽  
New World Monkeys ◽  
Infectious Agents ◽  
Sm Proteins ◽  
General Utility ◽  
Smn Complex ◽  
Survival Of Motor Neurons ◽  
Very High

ABSTRACT The lymphotropic Herpesvirus saimiri (HVS) causes acute leukemia, T-cell lymphoma, and death in New World monkeys. HVS encodes seven small RNAs (HSURs) of unknown function. The HSURs acquire host Sm proteins and assemble Sm cores similar to those found on the spliceosomal small nuclear RNPs (snRNPs). Here we show that, like host snRNPs, HSURs use the SMN (survival of motor neurons) complex to assemble Sm cores. The HSURs bind the SMN complex directly and with very high affinity, similar to or higher than that of host snRNAs, and can outcompete host snRNAs for SMN-dependent assembly into RNPs. These observations highlight the general utility of the SMN complex for RNP assembly and suggest that infectious agents that engage the SMN complex may burden SMN-dependent pathways, possibly leading to a deleterious reduction in available SMN complex for essential host functions.

scholarly journals INNOVATIVE THERAPIES IN GENETIC DISEASES: SPINAL MUSCULAR ATROPHY

2021 ◽  
Vol 70 (2) ◽  
pp. 108-113
Author(s):  
Elena-Silvia Shelby ◽  
◽  
Andrada Mirea ◽  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Pediatric Population ◽  
Genetic Diseases ◽  
Short Review ◽  
Progressive Muscle Weakness ◽  
Innovative Therapies ◽  
Biallelic Mutations ◽  
Congenital Neuromuscular Disease

Spinal muscular atrophy is a congenital neuromuscular disease characterized by the deterioration of the motor neurons located mainly in the anterior horns of the spinal cord, leading to progressive muscle weakness and atrophy. Globally, SMA is, after cystic fibrosis, the second cause of death due to a a genetic disease in the pediatric population. Over 95% of the total cases of SMA are represented by 5q SMA, caused by biallelic mutations in the SMN1 gene (5q13.2), the rest of the SMA types being called, generically, non-5q SMA. Currently, a few genetic targeted therapies are available for 5q SMA, while other innovative therapies are still in clinical trials. Early diagnosis and treatment of 5q SMA have an essential role in preventing the onset and evolution of symptoms and can save the life of the patient and prevent debilitating sequelae. This article aims to briefly describe the cause and symptomatology of 5q SMA as well as to make a short review of the genetic therapies available for this disease.

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