Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 30, Pages E4377-E4386Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1600015113
Keywords
endocytic trafficking; survival motor neuron; spinal muscular atrophy; C. elegans; infection
Categories
Funding
- NIH Office of Research Infrastructure Programs [P40 OD010440]
- SMA Foundation
- NIH NINDS Grant [NS066888, F31NS089201]
- NIH Grant [OD010943]
- Institutional Development Award (IDeA) from National Institute of General Medical Sciences of the National Institutes of Health [P20GM103423]
- Ruth L. Kirschstein National Research Service Award from National Institute of Neurological Disorders and Stroke [F32NS064870]
- National Institute of General Medical Sciences [P30GM103410]
- NICHD Grant for RFK-IDDRC at Albert Einstein College of Medicine [P30 HD71593]
- [P01NS065719]
- [R01NS043097]
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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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