Decreased function of survival motor neuron protein impairs endocytic pathways.
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Date
2016-07-26ICR Author
Author
Dimitriadi, M
Derdowski, A
Kalloo, G
Maginnis, MS
O'Hern, P
Bliska, B
Sorkaç, A
Nguyen, KCQ
Cook, SJ
Poulogiannis, G
Atwood, WJ
Hall, DH
Hart, AC
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Motor Neurons
Synapses
Cells, Cultured
Animals
Animals, Genetically Modified
Humans
Caenorhabditis elegans
Muscular Atrophy, Spinal
Disease Models, Animal
Caenorhabditis elegans Proteins
Signal Transduction
Endocytosis
RNA Interference
Amino Acid Sequence
Survival of Motor Neuron 1 Protein
Research team
Signalling & Cancer Metabolism
Language
eng
Date accepted
2016-06-02
License start date
2016-07-11
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2016, 113 (30), pp. E4377 - E4386
Publisher
NATL ACAD SCIENCES