scholarly journals Impairment of the neurotrophic signaling hub B-Raf contributes to motoneuron degeneration in spinal muscular atrophy

2021 ◽  
Vol 118 (18) ◽  
pp. e2007785118
Author(s):  
Niko Hensel ◽  
Federica Cieri ◽  
Pamela Santonicola ◽  
Ines Tapken ◽  
Tobias Schüning ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Signaling Pathways ◽  
Muscular Atrophy ◽  
Direct Interaction ◽  
Erk Pathway ◽  
Motoneuron Survival ◽  
C Elegans ◽  
Protein Levels ◽  
Approved Drugs ◽  
Motoneuron Degeneration

Spinal muscular atrophy (SMA) is a motoneuron disease caused by deletions of the Survival of Motoneuron 1 gene (SMN1) and low SMN protein levels. SMN restoration is the concept behind a number of recently approved drugs which result in impressive yet limited effects. Since SMN has already been enhanced in treated patients, complementary SMN-independent approaches are needed. Previously, a number of altered signaling pathways which regulate motoneuron degeneration have been identified as candidate targets. However, signaling pathways form networks, and their connectivity is still unknown in SMA. Here, we used presymptomatic SMA mice to elucidate the network of altered signaling in SMA. The SMA network is structured in two clusters with AKT and 14-3-3 ζ/δ in their centers. Both clusters are connected by B-Raf as a major signaling hub. The direct interaction of B-Raf with 14-3-3 ζ/δ is important for an efficient neurotrophic activation of the MEK/ERK pathway and crucial for motoneuron survival. Further analyses in SMA mice revealed that both proteins were down-regulated in motoneurons and the spinal cord with B-Raf being reduced at presymptomatic stages. Primary fibroblasts and iPSC-derived motoneurons from SMA patients both showed the same pattern of down-regulation. This mechanism is conserved across species since a Caenorhabditis elegans SMA model showed less expression of the B-Raf homolog lin-45. Accordingly, motoneuron survival was rescued by a cell autonomous lin-45 expression in a C. elegans SMA model resulting in improved motor functions. This rescue was effective even after the onset of motoneuron degeneration and mediated by the MEK/ERK pathway.

SMN mRNA and protein levels in peripheral blood

Neurology ◽  
2006 ◽  
Vol 66 (7) ◽  
pp. 1067-1073 ◽  
Author(s):  
C. J. Sumner ◽  
S. J. Kolb ◽  
G. G. Harmison ◽  
N. O. Jeffries ◽  
K. Schadt ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Spinal Muscular Atrophy ◽  
Disease Severity ◽  
Peripheral Blood ◽  
Muscular Atrophy ◽  
Gene Copy ◽  
Blood Levels ◽  
Type I ◽  
Protein Levels ◽  
Smn Protein

Background: Clinical trials of drugs that increase SMN protein levels in vitro are currently under way in patients with spinal muscular atrophy.Objective: To develop and validate measures of SMN mRNA and protein in peripheral blood and to establish baseline SMN levels in a cohort of controls, carriers, and patients of known genotype, which could be used to follow response to treatment.Methods: SMN1 and SMN2 gene copy numbers were determined in blood samples collected from 86 subjects. Quantitative reverse transcription PCR was used to measure blood levels of SMN mRNA with and without exon 7. A cell immunoassay was used to measure blood levels of SMN protein.Results: Blood levels of SMN mRNA and protein were measured with high reliability. There was little variation in SMN levels in individual subjects over a 5-week period. Levels of exon 7-containing SMN mRNA and SMN protein correlated with SMN1 and SMN2 gene copy number. With the exception of type I SMA, there was no correlation between SMN levels and disease severity.Conclusion: SMN mRNA and protein levels can be reliably measured in the peripheral blood and used during clinical trials in spinal muscular atrophy, but these levels do not necessarily predict disease severity.

scholarly journals Temporal and tissue-specific variability of SMN protein levels in mouse models of spinal muscular atrophy

2018 ◽  
Vol 27 (16) ◽  
pp. 2851-2862 ◽  
Author(s):  
Ewout J N Groen ◽  
Elena Perenthaler ◽  
Natalie L Courtney ◽  
Crispin Y Jordan ◽  
Hannah K Shorrock ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Mouse Models ◽  
Muscular Atrophy ◽  
Tissue Specific ◽  
Protein Levels ◽  
Smn Protein

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.

scholarly journals Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCFSlmb degron

2018 ◽  
Vol 29 (2) ◽  
pp. 96-110 ◽  
Author(s):  
Kelsey M. Gray ◽  
Kevin A. Kaifer ◽  
David Baillat ◽  
Ying Wen ◽  
Thomas R. Bonacci ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Protein Isoforms ◽  
Survival Motor Neuron Protein ◽  
Protein Levels ◽  
Motor Neuron Protein ◽  
Smn Protein ◽  
Oligomerization Domain

SMN protein levels inversely correlate with the severity of spinal muscular atrophy. The SCFSlmbE3 ligase complex interacts with a degron embedded within the C-terminal self-oligomerization domain of SMN. The findings elucidate a model whereby accessibility of the SMN degron is regulated by self-multimerization.

scholarly journals The E3 ubiquitin ligase mind bomb 1 ubiquitinates and promotes the degradation of survival of motor neuron protein

2013 ◽  
Vol 24 (12) ◽  
pp. 1863-1871 ◽  
Author(s):  
Deborah Y. Kwon ◽  
Maria Dimitriadi ◽  
Barbara Terzic ◽  
Casey Cable ◽  
Anne C. Hart ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Ubiquitin Ligase ◽  
Cultured Cells ◽  
Muscular Atrophy ◽  
E3 Ubiquitin Ligase ◽  
Proteasome Inhibition ◽  
Protein Levels ◽  
Smn Protein ◽  
Survival Of Motor Neuron

Spinal muscular atrophy is an inherited motor neuron disease that results from a deficiency of the survival of motor neuron (SMN) protein. SMN is ubiquitinated and degraded through the ubiquitin proteasome system (UPS). We have previously shown that proteasome inhibition increases SMN protein levels, improves motor function, and reduces spinal cord, muscle, and neuromuscular junction pathology of spinal muscular atrophy (SMA) mice. Specific targets in the UPS may be more efficacious and less toxic. In this study, we show that the E3 ubiquitin ligase, mind bomb 1 (Mib1), interacts with and ubiquitinates SMN and facilitates its degradation. Knocking down Mib1 levels increases SMN protein levels in cultured cells. Also, knocking down the Mib1 orthologue improves neuromuscular function in Caenorhabditis elegans deficient in SMN. These findings demonstrate that Mib1 ubiquitinates and catalyzes the degradation of SMN, and thus represents a novel therapeutic target for SMA.

scholarly journals Automated screening ofC. elegansneurodegeneration mutants enabled by microfluidics and image analysis algorithms

2018 ◽  
Vol 10 (9) ◽  
pp. 539-548 ◽  
Author(s):  
Ivan de Carlos Cáceres ◽  
Daniel A. Porto ◽  
Ivan Gallotta ◽  
Pamela Santonicola ◽  
Josue Rodríguez-Cordero ◽  
...  
Keyword(s):  
Image Analysis ◽  
Spinal Muscular Atrophy ◽  
High Throughput ◽  
Muscular Atrophy ◽  
High Throughput Screen ◽  
C Elegans ◽  
Genetic Mechanisms ◽  
Automated Screening

A fully automated high-throughput screen usingC. elegansto investigate genetic mechanisms affecting spinal muscular atrophy (SMA).

scholarly journals Genetic modifiers ameliorate endocytic and neuromuscular defects in a model of spinal muscular atrophy

BMC Biology ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Melissa B. Walsh ◽  
Eva Janzen ◽  
Emily Wingrove ◽  
Seyyedmohsen Hosseinibarkooie ◽  
Natalia Rodriguez Muela ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Protein Complexes ◽  
Genetic Modifiers ◽  
Functional Connection ◽  
C Elegans ◽  
Hnrnp F ◽  
Smn Protein ◽  
Survival Of Motor Neuron

Abstract Background Understanding the genetic modifiers of neurodegenerative diseases can provide insight into the mechanisms underlying these disorders. Here, we examine the relationship between the motor neuron disease spinal muscular atrophy (SMA), which is caused by reduced levels of the survival of motor neuron (SMN) protein, and the actin-bundling protein Plastin 3 (PLS3). Increased PLS3 levels suppress symptoms in a subset of SMA patients and ameliorate defects in SMA disease models, but the functional connection between PLS3 and SMN is poorly understood. Results We provide immunohistochemical and biochemical evidence for large protein complexes localized in vertebrate motor neuron processes that contain PLS3, SMN, and members of the hnRNP F/H family of proteins. Using a Caenorhabditis elegans (C. elegans) SMA model, we determine that overexpression of PLS3 or loss of the C. elegans hnRNP F/H ortholog SYM-2 enhances endocytic function and ameliorates neuromuscular defects caused by decreased SMN-1 levels. Furthermore, either increasing PLS3 or decreasing SYM-2 levels suppresses defects in a C. elegans ALS model. Conclusions We propose that hnRNP F/H act in the same protein complex as PLS3 and SMN and that the function of this complex is critical for endocytic pathways, suggesting that hnRNP F/H proteins could be potential targets for therapy development.

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