Mutations in Caenorhabditis elegans cytoplasmic dynein components reveal specificity of neuronal retrograde cargo.
We describe Caenorhabditis elegans dynein complex mutants, which misaccumulate synaptic proteins at the ends of neuronal processes. Ultrastructural analysis revealed irregularly sized vesicles that likely represent accumulation of cargo. We propose that synaptobrevin, synaptotagmin, and UNC-104 are specific cargoes of the dynein complex. Many cargoes link to dynein via interactions between dynactin and vesicle-associated spectrin. However, loss of spectrin results in only mild and occasional defects in synaptobrevin localization. Thus, the dynein-dynactin complex shows neuronal cargo selectivity without spectrin being a critical component of cargo binding. We observed parallels to progressive motor neuron disease symptoms in these animals. With age, neuronal misaccumulations increase in size and frequency; locomotion becomes progressively slower; and life span is shortened. These mutants provide a model to assess whether defects in transport of specific cargo mediate neuronal dysfunction.
Koushika
Sandhya P
SP
Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Schaefer
Anneliese M
AM
Vincent
Rose
R
Willis
John H
JH
Bowerman
Bruce
B
Nonet
Michael L
ML
D000375:Aging / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins; D003593:Cytoplasm / Q000378:metabolism*; D018450:Disease Progression; D000072159:Dynactin Complex; D004398:Dyneins / Q000235:genetics* / Q000378:metabolism; D008124:Locomotion / Q000235:genetics; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009422:Nervous System Diseases / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010641:Phenotype; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D050683:R-SNARE Proteins; D013049:Spectrin / Q000235:genetics; D015996:Survival Rate; D013572:Synaptic Vesicles / Q000378:metabolism / Q000648:ultrastructure; D050857:Synaptotagmins
D029742:Caenorhabditis elegans Proteins; D002135:Calcium-Binding Proteins; D000072159:Dynactin Complex; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D050683:R-SNARE Proteins; C423186:UNC-104 protein, C elegans; D013049:Spectrin; D050857:Synaptotagmins; D004398:Dyneins