Molecular basis for dyneinopathies reveals insight into dynein regulation and dysfunction

Cytoplasmic 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 '...

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Bibliographic Details
Published in:	eLife Vol. 8
Main Authors:	Marzo, Matthew G, Griswold, Jacqueline M, Ruff, Kristina M, Buchmeier, Rachel E, Fees, Colby P, Markus, Steven M
Format:	Journal Article
Language:	English
Published:	England eLife Science Publications, Ltd 31-07-2019 eLife Sciences Publications Ltd eLife Sciences Publications, Ltd
Subjects:	Biotechnology Cell Biology Cells (Biology) Defects Development and progression Disease Drug discovery Dynein dyneinopathy Dyneins - genetics Dyneins - metabolism Gene Expression Regulation Genetic aspects Humans malformations of cortical development Medical research Models, Theoretical Molecular biology Motor neuron diseases muscular dystrophy Mutant Proteins - genetics Mutant Proteins - metabolism Mutation Myosin Neurodegenerative diseases neurological disease Neuromuscular Diseases - pathology Neuromuscular Diseases - physiopathology Neurons Neuropathy Neurophysiology Phenotype Phenotypes Physiological aspects Proteins Retrograde transport Saccharomyces cerevisiae - genetics Saccharomyces cerevisiae - metabolism spindle positioning Suppression, Genetic Yeast United States United States > US dynein dyneinopathy muscular dystrophy cell biology neurological disease spindle positioning malformations of cortical development human S. cerevisiae
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Summary:	Cytoplasmic 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2050-084X 2050-084X
DOI:	10.7554/eLife.47246