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Front Mol Biosci. 2017 Jun 8;4:41. doi: 10.3389/fmolb.2017.00041. eCollection 2017.

Spinal Muscular Atrophy: From Defective Chaperoning of snRNP Assembly to Neuromuscular Dysfunction.

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Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of MaltaMsida, Malta.
Center for Molecular Medicine and Biobanking, University of MaltaMsida, Malta.
Institut de Génétique Moléculaire de Montpellier, Center National de la Recherche Scientifique-UMR 5535, Université de MontpellierMontpellier, France.


Spinal Muscular Atrophy (SMA) is a neuromuscular disorder that results from decreased levels of the survival motor neuron (SMN) protein. SMN is part of a multiprotein complex that also includes Gemins 2-8 and Unrip. The SMN-Gemins complex cooperates with the protein arginine methyltransferase 5 (PRMT5) complex, whose constituents include WD45, PRMT5 and pICln. Both complexes function as molecular chaperones, interacting with and assisting in the assembly of an Sm protein core onto small nuclear RNAs (snRNAs) to generate small nuclear ribonucleoproteins (snRNPs), which are the operating components of the spliceosome. Molecular and structural studies have refined our knowledge of the key events taking place within the crowded environment of cells and the numerous precautions undertaken to ensure the faithful assembly of snRNPs. Nonetheless, it remains unclear whether a loss of chaperoning in snRNP assembly, considered as a "housekeeping" activity, is responsible for the selective neuromuscular phenotype in SMA. This review thus shines light on in vivo studies that point toward disturbances in snRNP assembly and the consequential transcriptome abnormalities as the primary drivers of the progressive neuromuscular degeneration underpinning the disease. Disruption of U1 snRNP or snRNP assembly factors other than SMN induces phenotypes that mirror aspects of SMN deficiency, and splicing defects, described in numerous SMA models, can lead to a DNA damage and stress response that compromises the survival of the motor system. Restoring the correct chaperoning of snRNP assembly is therefore predicted to enhance the benefit of SMA therapeutic modalities based on augmenting SMN expression.


SMN-Gemins complex; amyotrophic lateral sclerosis (ALS); missplicing; motor neuron disease (MND); snRNP assembly; spinal muscular atrophy (SMA); spliceosome; survival motor neuron

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