Molecular basis for dyneinopathies reveals insight into dynein regulation and dysfunction

ELife
Matthew G. MarzoSteven M. Markus

Abstract

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.

References

Oct 1, 1989·Journal of the Neurological Sciences·H Hayashi, S Kato
Nov 1, 1993·Proceedings of the National Academy of Sciences of the United States of America·Y Y LiK Bloom
Dec 1, 1993·Proceedings of the National Academy of Sciences of the United States of America·D EshelI R Gibbons
Oct 1, 1996·Molecular and Cellular Biology·E Bi, J R Pringle
Jun 22, 2000·Yeast·V V Kushnirov
Sep 13, 2000·Nature·H YinA Bretscher
Dec 21, 2000·The Journal of Cell Biology·R A Heil-ChapdelaineJ A Cooper
Feb 7, 2001·The Journal of Cell Biology·S Song, K S Lee
Mar 29, 2001·Genes & Development·A Wynshaw-Boris, M J Gambello
Jan 17, 2002·Cell·Davide SalinaBrian Burke
Feb 5, 2003·The Journal of Cell Biology·Wei-Lih LeeJohn A Cooper
Apr 16, 2003·The Journal of Cell Biology·Chun-Hong XiaLawrence S B Goldstein
May 6, 2003·Science·Majid HafezparastElizabeth M C Fisher
Sep 3, 2004·Molecular Biology of the Cell·Oliver I WagnerErika L F Holzbaur
Jan 12, 2005·The Journal of Cell Biology·Wei-Lih LeeJohn A Cooper
Feb 25, 2005·The Journal of Cell Biology·Yan HePeter W Baas
Mar 5, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Orly LazarovSangram S Sisodia
Jun 21, 2005·Nature Cell Biology·Jun LiJohn A Cooper
Jun 28, 2005·Nature Genetics·Brinda RavikumarDavid C Rubinsztein
Jan 28, 2006·PLoS Genetics·K Kevin PfisterElizabeth M C Fisher
May 30, 2006·Biochimica Et Biophysica Acta·Erica Chevalier-Larsen, Erika L F Holzbaur
Jul 29, 2006·Cell·Samara L Reck-PetersonRonald D Vale
Sep 29, 2006·Annals of Neurology·Hong Lin, William W Schlaepfer
Jul 10, 2007·Nature Neuroscience·Jin-Wu TsaiRichard B Vallee
Dec 28, 2007·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Xiang-Jun ChenBrian Popko
Jan 29, 2008·Traffic·Jeffrey K MooreJohn A Cooper
Feb 3, 2009·Current Biology : CB·Steven M MarkusWei-Lih Lee
Mar 13, 2009·Proceedings of the National Academy of Sciences of the United States of America·Jeffrey K MooreJohn A Cooper

❮ Previous
Next ❯

Citations

Sep 11, 2019·Nature Chemical Biology·Richard J McKenney
Nov 17, 2020·Frontiers in Cell and Developmental Biology·Xin Xiang, Rongde Qiu
May 16, 2021·American Journal of Medical Genetics. Part a·Hormos Salimi DafsariSebahattin Cirak
Nov 23, 2021·Investigative Ophthalmology & Visual Science·Tiffanie M DahlWolfgang Baehr
Nov 27, 2021·American Journal of Medical Genetics. Part a·Hui-Lin ChinSteven J M Jones

❮ Previous
Next ❯

Methods Mentioned

BETA
dissection
motility assays
Fluorescence
fluorescence imaging
PCR
gel filtration
fluorescence microscopy

Software Mentioned

ImageJ
NIS Elements
Matlab
Graphpad Prism

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.