Decreased function of survival motor neuron protein impairs endocytic pathways

Maria Dimitriadi, Aaron Derdowski, Geetika Kalloo, Melissa S. Maginnis, Patrick O'hern, Bryn Bliska, Altar Sorkaç, Ken C.Q. Nguyen, Steven J. Cook, George Poulogiannis, Walter J. Atwood, David H. Hall, Anne C. Hart

Research output: Contribution to journalArticle

26 Scopus citations

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 interactionswere consistentwith 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.

Original languageEnglish (US)
Pages (from-to)E4377-4386
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number30
DOIs
StatePublished - Jul 26 2016

Keywords

  • C. elegans
  • Endocytic trafficking
  • Infection
  • Spinal muscular atrophy
  • Survival motor neuron

ASJC Scopus subject areas

  • General

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    Dimitriadi, M., Derdowski, A., Kalloo, G., Maginnis, M. S., O'hern, P., Bliska, B., Sorkaç, A., Nguyen, K. C. Q., Cook, S. J., Poulogiannis, G., Atwood, W. J., Hall, D. H., & Hart, A. C. (2016). Decreased function of survival motor neuron protein impairs endocytic pathways. Proceedings of the National Academy of Sciences of the United States of America, 113(30), E4377-4386. https://doi.org/10.1073/pnas.1600015113