Molecular mechanisms in spinal muscular atrophy: models and perspectives

Spinal muscular atrophy is an autosomal-recessive disorder that is caused by homozygous mutations or deletion of the telomeric copy of the survival of motor neurone (SMN) gene on human chromosome 5q13. The SMN gene is present as an inverted repeat in this chromosomal region, and both SMN genes are expressed. They differ by the preferential expression of a full-length transcript from the telomeric copy and a truncated SMN protein from the centromeric SMN gene, which lacks the carboxyl-terminal portions of the protein encoded by exon 7. The SMN protein is part of multiprotein complexes in the cytoplasm and the nucleus that are involved in spliceosomal small-nuclear RNP assembly. This function depends on interaction with spliceosomal Sm core proteins. Recent data have also shown that the SMN protein interacts with RNA polymerase II, thus implying additional functions in messenger RNA transcription, possibly by assembly of RNA polymerase II transcription complexes. Thus, the SMN protein is involved in critical steps of messenger RNA transcription and processing, and current research efforts are directed at identifying the specificity of these defects for the pathophysiological changes in motor neurones that occur in spinal muscular atrophy.

[1]  G. Dreyfuss,et al.  The Spinal Muscular Atrophy Disease Gene Product, SMN, and Its Associated Protein SIP1 Are in a Complex with Spliceosomal snRNP Proteins , 1997, Cell.

[2]  C. Lorson,et al.  An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN. , 2000, Human molecular genetics.

[3]  R. Götz,et al.  The neuronal apoptosis inhibitory protein suppresses neuronal differentiation and apoptosis in PC12 cells. , 2000, Human molecular genetics.

[4]  A. Shevchenko,et al.  Gemin4. A novel component of the SMN complex that is found in both gems and nucleoli. , 2000, The Journal of cell biology.

[5]  A. Smith,et al.  Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[6]  R. Lührmann,et al.  The C-terminal RG Dipeptide Repeats of the Spliceosomal Sm Proteins D1 and D3 Contain Symmetrical Dimethylarginines, Which Form a Major B-cell Epitope for Anti-Sm Autoantibodies* , 2000, The Journal of Biological Chemistry.

[7]  Arnold Munnich,et al.  Correlation between severity and SMN protein level in spinal muscular atrophy , 1997, Nature Genetics.

[8]  T. Crawford.  From enigmatic to problematic , 1996, Neurology.

[9]  H. Thoenen,et al.  Inactivation of bcl-2 Results in Progressive Degeneration of Motoneurons, Sympathetic and Sensory Neurons during Early Postnatal Development , 1996, Neuron.

[10]  E. Kremmer,et al.  Characterization of DP103, a Novel DEAD Box Protein That Binds to the Epstein-Barr Virus Nuclear Proteins EBNA2 and EBNA3C* , 1999, The Journal of Biological Chemistry.

[11]  Steven Theroux,et al.  Spinal muscular atrophy disrupts the interaction of ZPR1 with the SMN protein , 2001, Nature Cell Biology.

[12]  C. Lorson,et al.  SMN oligomerization defect correlates with spinal muscular atrophy severity , 1998, Nature Genetics.

[13]  S. Stamm,et al.  Htra2-beta 1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 (SMN2). , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[14]  C. Ponting,et al.  Analysis of mutations in the tudor domain of the survival motor neuron protein SMN , 1999, European Journal of Human Genetics.

[15]  J. Melki,et al.  Interferons and IRF-1 Induce Expression of the Survival Motor Neuron (SMN) Genes , 2000, Molecular medicine.

[16]  Douglas A. Kerr,et al.  Survival motor neuron protein modulates neuron-specific apoptosis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[17]  B. Séraphin,et al.  The Schizosaccharomyces pombe protein Yab8p and a novel factor, Yip1p, share structural and functional similarity with the spinal muscular atrophy-associated proteins SMN and SIP1. , 2000, Human molecular genetics.

[18]  Denise S Walker,et al.  The Caenorhabditis elegans orthologue of the human gene responsible for spinal muscular atrophy is a maternal product critical for germline maturation and embryonic viability. , 1999, Human molecular genetics.

[19]  I. Miguel-Aliaga,et al.  Disruption of SMN function by ectopic expression of the human SMN gene in Drosophila , 2000, FEBS letters.

[20]  N. Gilbert,et al.  SMN gene duplication and the emergence of the SMN2 gene occurred in distinct hominids: SMN2 is unique to Homo sapiens , 2001, Human Genetics.

[21]  C. Lorson,et al.  A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[22]  L. Kunkel,et al.  The mouse region syntenic for human spinal muscular atrophy lies within the Lgn1 critical interval and contains multiple copies of Naip exon 5. , 1996, Genomics.

[23]  G. Dreyfuss,et al.  The SMN–SIP1 Complex Has an Essential Role in Spliceosomal snRNP Biogenesis , 1997, Cell.

[24]  J. McPherson,et al.  A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. , 1999, Human molecular genetics.

[25]  J. Melki,et al.  Deletion of Murine SMN Exon 7 Directed to Skeletal Muscle Leads to Severe Muscular Dystrophy , 2001, The Journal of cell biology.

[26]  G. Meister,et al.  Characterization of a nuclear 20S complex containing the survival of motor neurons (SMN) protein and a specific subset of spliceosomal Sm proteins. , 2000, Human molecular genetics.

[27]  J. Melki,et al.  The role of the SMN gene in proximal spinal muscular atrophy. , 1998, Human molecular genetics.

[28]  M. Gurney,et al.  Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. , 1994, Science.

[29]  A. MacKenzie,et al.  Spinal muscular atrophy: molecular pathophysiology. , 1999, Current opinion in neurology.

[30]  M. Sendtner,et al.  Does the survival motor neuron protein (SMN) interact with Bcl-2? , 2000, Journal of medical genetics.

[31]  H. Jockusch,et al.  A Role for Polyproline Motifs in the Spinal Muscular Atrophy Protein SMN , 1999, The Journal of Biological Chemistry.

[32]  G. Stier,et al.  SMN Tudor domain structure and its interaction with the Sm proteins , 2001, Nature Structural Biology.

[33]  U. Monani,et al.  The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(-/-) mice and results in a mouse with spinal muscular atrophy. , 2000, Human molecular genetics.

[34]  A. Shevchenko,et al.  Gemin3: A novel DEAD box protein that interacts with SMN, the spinal muscular atrophy gene product, and is a component of gems. , 1999, The Journal of cell biology.

[35]  G. Dreyfuss,et al.  SMN, the product of the spinal muscular atrophy gene, binds preferentially to dimethylarginine-containing protein targets. , 2001, Molecular cell.

[36]  M. Luca,et al.  Subcellular localization and axonal transport of the survival motor neuron (SMN) protein in the developing rat spinal cord. , 2000, Human molecular genetics.

[37]  J. Weissenbach,et al.  Identification and characterization of a spinal muscular atrophy-determining gene , 1995, Cell.

[38]  Fricker,et al.  Mouse model of spinal muscular atrophy. , 2000, Drug discovery today.

[39]  Noriko Yasuhara,et al.  Synergistic anti-apoptotic activity between Bcl-2 and SMN implicated in spinal muscular atrophy , 1997, Nature.

[40]  M. Brasch,et al.  Direct interaction of Smn with dp103, a putative RNA helicase: a role for Smn in transcription regulation? , 2000, Human molecular genetics.

[41]  B. Wirth,et al.  Co-regulation of survival of motor neuron (SMN) protein and its interactor SIP1 during development and in spinal muscular atrophy. , 2001, Human molecular genetics.

[42]  Klaus Zerres,et al.  Identification of a candidate modifying gene for spinal muscular atrophy by comparative genomics , 1998, Nature Genetics.

[43]  K. Davies,et al.  Characterization of the Schizosaccharomyces pombe orthologue of the human survival motor neuron (SMN) protein. , 2000, Human molecular genetics.

[44]  B. Schrank,et al.  Reduced survival motor neuron (Smn) gene dose in mice leads to motor neuron degeneration: an animal model for spinal muscular atrophy type III. , 2000, Human molecular genetics.

[45]  G. Šimić,et al.  Ultrastructural Analysis and TUNEL Demonstrate Motor Neuron Apoptosis in Werdnig‐Hoffmann Disease , 2000, Journal of neuropathology and experimental neurology.

[46]  G. Dreyfuss,et al.  A Novel Function for SMN, the Spinal Muscular Atrophy Disease Gene Product, in Pre-mRNA Splicing , 1998, Cell.

[47]  G. Dreyfuss,et al.  A cell system with targeted disruption of the SMN gene: functional conservation of the SMN protein and dependence of Gemin2 on SMN. , 2001, The Journal of biological chemistry.

[48]  B. Pettmann,et al.  Death of Motoneurons Induced by Trophic Deprivation or by Excitotoxicity Is Not Prevented by Overexpression of SMN , 2001, Neurobiology of Disease.

[49]  P Miniou,et al.  Nuclear targeting defect of SMN lacking the C-terminus in a mouse model of spinal muscular atrophy. , 2000, Human molecular genetics.

[50]  G. Dreyfuss,et al.  The survival motor neuron protein of Schizosacharomyces pombe. Conservation of survival motor neuron interaction domains in divergent organisms. , 2000, The Journal of biological chemistry.

[51]  M. Mann,et al.  A Functional Interaction between the Survival Motor Neuron Complex and RNA Polymerase II , 2001, The Journal of cell biology.