title: Disruption of snRNP biogenesis factors Tgs1 and pICln induces phenotypes that mirror aspects of SMN-Gemins complex perturbation in Drosophila, providing new insights into spinal muscular atrophy.
abstract: The neuromuscular disorder, spinal muscular atrophy (SMA), results from insufficient levels of the survival motor neuron (SMN) protein. Together with Gemins 2-8 and Unrip, SMN forms the large macromolecular SMN-Gemins complex, which is known to be indispensable for chaperoning the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs). It remains unclear whether disruption of this function is responsible for the selective neuromuscular degeneration in SMA. In the present study, we first show that loss of wmd, the Drosophila Unrip orthologue, has a negative impact on the motor system. However, due to lack of a functional relationship between wmd/Unrip and Gemin3, it is likely that Unrip joined the SMN-Gemins complex only recently in evolution. Second, we uncover that disruption of either Tgs1 or pICln, two cardinal players in snRNP biogenesis, results in viability and motor phenotypes that closely resemble those previously uncovered on loss of the constituent members of the SMN-Gemins complex. Interestingly, overexpression of both factors leads to motor dysfunction in Drosophila, a situation analogous to that of Gemin2. Toxicity is conserved in the yeast S. pombe where pICln overexpression induces a surplus of Sm proteins in the cytoplasm, indicating that a block in snRNP biogenesis is partly responsible for this phenotype. Importantly, we show a strong functional relationship and a physical interaction between Gemin3 and either Tgs1 or pICln. We propose that snRNP biogenesis is the pathway connecting the SMN-Gemins complex to a functional neuromuscular system, and its disturbance most likely leads to the motor dysfunction that is typical in SMA.
authors.affiliation: Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta; Centre for Molecular Medicine and Biobanking, Biomedical Sciences Building, University of Malta, Msida, Malta; Institut de Génétique Moléculaire de Montpellier, CNRS-UMR5535, Université Montpellier 1 and 2, Montpellier, France.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Borg
authors.affiliation: Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta; Centre for Molecular Medicine and Biobanking, Biomedical Sciences Building, University of Malta, Msida, Malta.
authors.forename: Benji
authors.initials: B
authors.lastname: Fenech Salerno
authors.affiliation: Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta; Centre for Molecular Medicine and Biobanking, Biomedical Sciences Building, University of Malta, Msida, Malta.
authors.forename: Neville
authors.initials: N
authors.lastname: Vassallo
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS-UMR5535, Université Montpellier 1 and 2, Montpellier, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Bordonne
authors.affiliation: Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta; Centre for Molecular Medicine and Biobanking, Biomedical Sciences Building, University of Malta, Msida, Malta. Electronic address: ruben.cauchi@um.edu.mt.
authors.forename: Ruben J
authors.initials: RJ
authors.lastname: Cauchi
mesh_terms: D000818:Animals; D003593:Cytoplasm / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D009046:Motor Neurons / Q000378:metabolism*; D010641:Phenotype; D017411:Ribonucleoproteins, Small Nuclear / Q000378:metabolism*; D055532:SMN Complex Proteins / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D017411:Ribonucleoproteins, Small Nuclear; D055532:SMN Complex Proteins
keywords: Gemin2; Gemin3; SMN complex; Strap; Tgs1; Unrip; motor neuron disease; pICln; snRNP assembly; spinal muscular atrophy; trimethylguanosine synthase 1; wmd