Molecular basis for dyneinopathies reveals insight into dynein regulation and dysfunction

• 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
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.47246

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.