title: Decreased function of survival motor neuron protein impairs endocytic pathways.
abstract: 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.
authors.affiliation: Department of Neuroscience, Brown University, Providence, RI 02912; Department of Biological and Environmental Sciences, University of Hertfordshire, Hatfield AL10 9AB, United Kingdom;
authors.forename: Maria
authors.initials: M
authors.lastname: Dimitriadi
authors.affiliation: Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912;
authors.forename: Aaron
authors.initials: A
authors.lastname: Derdowski
authors.affiliation: Department of Neuroscience, Brown University, Providence, RI 02912;
authors.forename: Geetika
authors.initials: G
authors.lastname: Kalloo
authors.affiliation: Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912; Department of Molecular and Biomedical Sciences, University of Maine, Orono, ME 04469;
authors.forename: Melissa S
authors.initials: MS
authors.lastname: Maginnis
authors.affiliation: Department of Neuroscience, Brown University, Providence, RI 02912;
authors.forename: Patrick
authors.initials: P
authors.lastname: O'Hern
authors.affiliation: Department of Neuroscience, Brown University, Providence, RI 02912;
authors.forename: Bryn
authors.initials: B
authors.lastname: Bliska
authors.affiliation: Department of Neuroscience, Brown University, Providence, RI 02912;
authors.forename: Altar
authors.initials: A
authors.lastname: Sorkaç
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Ken C Q
authors.initials: KC
authors.lastname: Nguyen
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Cook
authors.affiliation: Chester Beatty Labs, The Institute of Cancer Research, London SW3 6JB, United Kingdom.
authors.forename: George
authors.initials: G
authors.lastname: Poulogiannis
authors.affiliation: Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912;
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Atwood
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: David H
authors.initials: DH
authors.lastname: Hall
authors.affiliation: Department of Neuroscience, Brown University, Providence, RI 02912; anne_hart@brown.edu.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Hart
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004705:Endocytosis / Q000235:genetics*; D006801:Humans; D009046:Motor Neurons / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics*; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics* / Q000378:metabolism; D013569:Synapses / Q000235:genetics / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D055533:Survival of Motor Neuron 1 Protein
keywords: C. elegans; endocytic trafficking; infection; spinal muscular atrophy; survival motor neuron