The Spinal Muscular Atrophy Disease Protein SMN Is Linked to the Golgi Network

Ting, Chen-Hung; Wen, Hsin Lan; Liu, Hui Chun; Hsieh-Li, Hsiu Mei; Li, Hung; Lin‐Chao, Sue

doi:10.1371/journal.pone.0051826

Cited by 33 publications

(29 citation statements)

References 36 publications

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“…Interestingly, some of the vesicles appear to be immediately adjacent to granular structures of a similar size. This is consistent with recent electron microscopic analysis of SMN-containing structures associated with the Golgi complex in mouse motor-neuron-like NSC34 cells (Ting et al, 2012).…”

Section: Research Articlesupporting

confidence: 93%

Time-resolved quantitative proteomics implicates the core snRNP protein, SmB, together with the Survival of Motor Neuron protein, in neural trafficking

Prescott

Bales

James

et al. 2013

Journal of Cell Science

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The biogenesis of splicing snRNPs (small nuclear ribonucleoproteins) is a complex process, beginning and ending in the nucleus of the cell but including key stages that take place in the cytoplasm. In particular, the SMN (survival motor neuron) protein complex is required for addition of the core Sm proteins to the snRNP. Insufficiency of SMN results in the inherited neurodegenerative condition, spinal muscular atrophy (SMA). Details of the physical organization of the cytoplasmic stages of snRNP biogenesis are unknown. Here, we use timeresolved quantitative proteomics to identify proteins that associate preferentially with either newly assembled or mature splicing snRNPs. We identified highly mobile SmB protein-trafficking vesicles in neural cells, which are dependent on the cellular levels of SMN and SmB for their morphology and mobility. We propose that these represent a family of related vesicles, some of which play a role in snRNP biogenesis and some that might play more diverse roles in cellular RNA metabolism.

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Section: Research Articlesupporting

confidence: 93%

Time-resolved quantitative proteomics implicates the core snRNP protein, SmB, together with the Survival of Motor Neuron protein, in neural trafficking

Prescott

Bales

James

et al. 2013

Journal of Cell Science

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“…SMN directly binds and is transported within axons with the alpha subunit of the coat protein 1 (COPI), a critical player in intracellular vesicular trafficking. COPI can be found on Golgi, ER, and MVB membranes, and COPI loss results in defective endosomal function (70)(71)(72). Alternatively, the functional interaction between SMN, Plastin 3, and actin might play a role in the endocytic pathway defects observed when SMN levels are depleted.…”

Section: Smn-depleted Cells Are Resistant To Viral Endocytosis-dependentmentioning

confidence: 99%

Decreased function of survival motor neuron protein impairs endocytic pathways

Dimitriadi

Derdowski

Kalloo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Spinal muscular atrophy (SMA) is caused by depletion of the ubiquitously expressed survival motor neuron (SMN) protein, with 1 in 40 Caucasians being heterozygous for a disease allele. SMN is critical for the assembly of numerous ribonucleoprotein complexes, yet it is still unclear how reduced SMN levels affect motor neuron function. Here, we examined the impact of SMN depletion in Caenorhabditis elegans and found that decreased function of the SMN ortholog SMN-1 perturbed endocytic pathways at motor neuron synapses and in other tissues. Diminished SMN-1 levels caused defects in C. elegans neuromuscular function, and smn-1 genetic interactions were consistent with an endocytic defect. Changes were observed in synaptic endocytic proteins when SMN-1 levels decreased. At the ultrastructural level, defects were observed in endosomal compartments, including significantly fewer docked synaptic vesicles. Finally, endocytosis-dependent infection by JC polyomavirus (JCPyV) was reduced in human cells with decreased SMN levels. Collectively, these results demonstrate for the first time, to our knowledge, that SMN depletion causes defects in endosomal trafficking that impair synaptic function, even in the absence of motor neuron cell death.endocytic trafficking | survival motor neuron | spinal muscular atrophy | C. elegans | infection S pinal muscular atrophy (SMA) is one of the most severe neuromuscular diseases of childhood, with an incidence of 1 in 10,000 live births and a high carrier frequency of roughly 1 in 40 Caucasians (1-3). SMA is caused by reduced levels of the ubiquitously expressed survival of motor neuron (SMN) protein and results in degeneration of α-spinal cord motor neurons, muscle weakness, and/or death. Two human genes encode the SMN protein, SMN1 and SMN2. SMA alleles arise at relatively high frequency due to small intrachromosomal de novo rearrangements including the SMN1 locus (4). Patients often carry homozygous SMN1 deletions, although missense and nonsense alleles exist (5). Multiple copies of SMN2 rarely compensate for loss of SMN1 due to a C > T nucleotide change in SMN2 exon 7 that perturbs pre-mRNA splicing and results in a truncated protein of diminished function and stability (SMNΔ7) (5-9).SMN has numerous roles and interacts with various proteins, yet it remains unclear which interactions are most pertinent to SMA pathogenesis. As a component of the Gemin complex, SMN is required for biogenesis of small nuclear ribonucleoprotein (snRNP) particles critical for pre-mRNA splicing (10-12). Furthermore, SMN is needed for stress granule formation (13,14), is found in RNP granules moving through neuronal processes, and is part of RNP complexes implicated in synaptic local translation (15)(16)(17)(18)(19)(20). Additional roles for SMN, in transcription (21), in the PTEN-mediated protein synthesis pathway (22), in translational control (23), and in cell proliferation/differentiation (24), have been described. Importantly, no consensus has been reached regarding the cellular and molecular pathways wh...

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“…whereas over-expressing -cop increases neurite length in smn-depleted NSC34 cells [118,120]. These pieces of evidence further demonstrate there is a direct link between motor neurone vulnerability and axonal SMN.…”

Section: Accepted Manuscriptmentioning

confidence: 61%

“…SMN/ -cop granules are found in neurites and this association is likely to have begun in the Golgi apparatus [118,119]. Knockdown of -cop causes SMN accumulation in the Golgi…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Spinal muscular atrophy: Factors that modulate motor neurone vulnerability

Simpson

Highley

et al. 2017

Neurobiology of Disease

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Spinal muscular atrophy (SMA), a leading genetic cause of infant death, is a neurodegenerative disease characterised by the selective loss of particular groups of motor neurones in the anterior horn of the spinal cord with concomitant muscle weakness. To date, no effective treatment is available, however, there are ongoing clinical trials are in place which promise much for the future. However, there remains an ongoing problem in trying to link a single gene loss to motor neurone degeneration. Fortunately, given successful disease models that have been established and intensive studies on SMN functions in the past ten years, we are fast approaching the stage of identifying the underlying mechanisms of SMA pathogenesis Here we discuss potential disease modifying factors on motor neurone vulnerability, in the belief that these factors give insight into the pathological mechanisms of SMA and therefore possible therapeutic targets. Keywords:Selective vulnerability, SMA, SMN, disease modifier, motor neurone disease ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T Highlights: Factors that influence vulnerability of motor neurons in SMA. SMA disease modification. Impact of surrounding cells on neuronal death. Precise molecular defects in SMA; mRNA splicing and miRNA interactions. Cytoskeletal stability and axonal transport effects.

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The Spinal Muscular Atrophy Disease Protein SMN Is Linked to the Golgi Network

Cited by 33 publications

References 36 publications

Time-resolved quantitative proteomics implicates the core snRNP protein, SmB, together with the Survival of Motor Neuron protein, in neural trafficking

Time-resolved quantitative proteomics implicates the core snRNP protein, SmB, together with the Survival of Motor Neuron protein, in neural trafficking

Decreased function of survival motor neuron protein impairs endocytic pathways

Spinal muscular atrophy: Factors that modulate motor neurone vulnerability

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