TY - JOUR
T1 - Decreased function of survival motor neuron protein impairs endocytic pathways
AU - Dimitriadi, Maria
AU - Derdowski, Aaron
AU - Kalloo, Geetika
AU - Maginnis, Melissa S.
AU - O'hern, Patrick
AU - Bliska, Bryn
AU - Sorkaç, Altar
AU - Nguyen, Ken C.Q.
AU - Cook, Steven J.
AU - Poulogiannis, George
AU - Atwood, Walter J.
AU - Hall, David H.
AU - Hart, Anne C.
N1 - Funding Information:
We thank the Kaplan, Jorgensen, and Zhen laboratories for advice on C. elegans fluorescent imaging and quantitation as well as Dr. M. McKeown for helpful discussions. The C. elegans Gene Knockout Consortium (NIH/National Human Genome Research Institute) and the National BioResource Project provided C. elegans strains. Additional strains were provided by the Caenorhabditis elegans consortium (CGC), funded by NIH Office of Research Infrastructure Programs (P40 OD010440). This work was supported by the SMA Foundation and NIH NINDS Grant NS066888 (to A.C.H.), NIH Grant OD010943 (to D.H.H.), NIH NINDS Grant F31NS089201 (to P.O.), and Institutional Development Award (IDeA) P20GM103423 from the National Institute of General Medical Sciences of the National Institutes of Health (to M.S.M.). Research in the W.J.A. laboratory is funded by Grants P01NS065719 and R01NS043097 (to W.J.A.) and Ruth L. Kirschstein National Research Service Award F32NS064870 (to M.S.M.) from the National Institute of Neurological Disorders and Stroke. Core facilities for the W.J.A. laboratory are supported by Grant P30GM103410 (to W.J.A.) from the National Institute of General Medical Sciences. Core facilities for electron microscopy at the D.H.H. laboratory are supported by NICHD Grant P30 HD71593 for the RFKIDDRC at Albert Einstein College of Medicine
PY - 2016/7/26
Y1 - 2016/7/26
N2 - 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.
AB - 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.
KW - C. elegans
KW - Endocytic trafficking
KW - Infection
KW - Spinal muscular atrophy
KW - Survival motor neuron
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U2 - 10.1073/pnas.1600015113
DO - 10.1073/pnas.1600015113
M3 - Article
C2 - 27402754
AN - SCOPUS:84979556428
SN - 0027-8424
VL - 113
SP - E4377-4386
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 30
ER -
