Molecular basis for dyneinopathies reveals insight into dynein regulation and dysfunction

eLife

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[1] Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, United States;Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, United States;

关键词: dynein;    neurological disease;    spindle positioning;    dyneinopathy;    muscular dystrophy;    malformations of cortical development;    Human;    S. cerevisiae;   

DOI  :  10.7554/eLife.47246

来源: publisher

【 摘 要 】

10.7554/eLife.47246.001Cytoplasmic dynein plays critical roles within the developing and mature nervous systems, including effecting nuclear migration, and retrograde transport of various cargos. Unsurprisingly, mutations in dynein are causative of various developmental neuropathies and motor neuron diseases. These ‘dyneinopathies’ define a broad spectrum of diseases with no known correlation between mutation identity and disease state. To circumvent complications associated with dynein studies in human cells, we employed budding yeast as a screening platform to characterize the motility properties of seventeen disease-correlated dynein mutants. Using this system, we determined the molecular basis for several classes of etiologically related diseases. Moreover, by engineering compensatory mutations, we alleviated the mutant phenotypes in two of these cases, one of which we confirmed with recombinant human dynein. In addition to revealing molecular insight into dynein regulation, our data provide additional evidence that the type of disease may in fact be dictated by the degree of dynein dysfunction.

【 授权许可】

CC BY