Mutations in Dynein Link Motor Neuron Degeneration to Defects in Retrograde Transport

Hafezparast, Majid; Klocke, Rainer; Ruhrberg, Christiana; Marquardt, Andreas; Ahmad‐Annuar, Azlina; Bowen, Samantha; Lalli, Giovanna; Witherden, Abi S.; Hummerich, Holger; Nicholson, Sharon J.; Morgan, Pamela J; Oozageer, Ravi; Priestley, John V.; Averill, Sharon; King, Von R.; Ball, Simon; Peters, Jo; Toda, Takashi; Yamamoto, Ayumu; Hiraoka, Yasushi; Augustin, Martin; Korthaus, Dirk; Wattler, Sigrid; Wabnitz, Philipp; Dickneite, Carmen; Lampel, Stefan; Boehme, Florian; Peraus, G.C.; Popp, Andreas; Rudelius, Martina; Schlegel, Jürgen; Fuchs, Helmut; Angelis, Martin Hrabě de; Schiavo, Giampietro; Shima, David T.; Russ, Andreas; Stumm, Gabriele; Martin, Joanne E.; Fisher, Elizabeth

doi:10.1126/science.1083129

Cited by 633 publications

(552 citation statements)

References 29 publications

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“…600112, http://www.ncbi.nlm.nih.gov/omim) mutations give rise to an AD form of axonal CMT, known as CMT2O. 63,64 Accordingly, heterozygous mice with an orthologous pathogenic mutation of DYNC1H1 have a marked reduction in dynein microtubule binding affinity and abnormal retrograde axon transport which produces a CMT-like motor and sensory neuropathy. 65,66 In addition, DYN-interacting proteins that function as cofactors or modulators of DYN function are identified to cause neuropathy.…”

Section: Axon Transport and Neuropathymentioning

confidence: 99%

Axon Transport and Neuropathy

Tourtellotte

2016

The American Journal of Pathology

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Peripheral neuropathies are highly prevalent and are most often associated with chronic disease, side effects from chemotherapy, or toxic-metabolic abnormalities. Neuropathies are less commonly caused by genetic mutations, but studies of the normal function of mutated proteins have identified particular vulnerabilities that often implicate mitochondrial dynamics and axon transport mechanisms. Hereditary sensory and autonomic neuropathies are a group of phenotypically related diseases caused by monogenic mutations that primarily affect sympathetic and sensory neurons. Here, I review evidence to indicate that many genetic neuropathies are caused by abnormalities in axon transport. Moreover, in hereditary sensory and autonomic neuropathies. There may be specific convergence on gene mutations that disrupt nerve growth factor signaling, upon which sympathetic and sensory neurons critically depend. (Am J Pathol 2016, 186: 489e499; http://dx

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Section: Axon Transport and Neuropathymentioning

confidence: 99%

Axon Transport and Neuropathy

Tourtellotte

2016

The American Journal of Pathology

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“…In two lines of mice, Legs at odd angles (Loa) and Cramping 1 (Cra1), mutations in the dynein heavy chain gene cause motor neuron disease, and neurons from these mice exhibit a defect in the fast component of retrograde transport in vitro [37]. The Loa mice also exhibit an early-onset sensory neuropathy [38].…”

Section: Retrograde Transport and Neurodegenerationmentioning

confidence: 99%

Action in the axon: generation and transport of signaling endosomes

Cosker

Courchesne

Segal

2008

Current Opinion in Neurobiology

138

137

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Neurons extend axonal processes over long distances, necessitating efficient transport mechanisms to convey target-derived neurotrophic survival signals from remote distal axons to cell bodies. Retrograde transport, powered by dynein motors, supplies cell bodies with survival signals in the form of "signaling endosomes". In this review, we will discuss new advances in our understanding of the motor proteins that bind to and move signaling components in a retrograde direction, and discuss mechanisms that might specify distinct neuronal responses to spatially restricted neurotrophin signals. Disruption of retrograde transport leads to a variety of neurodegenerative diseases, highlighting the role of retrograde transport of signaling endosomes for axonal maintenance and the importance of efficient transport for neuronal survival and function. Retrograde axonal transport mechanismsNeurons extend long axons to contact post-synaptic targets far removed from the neuronal cell body. Hence long-range communication between the nerve ending and the cell body is essential for axonal pathfinding, target innervation, plasticity and survival. The neurotrophin family, including nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin 3 or 4 (NT-3 and NT-4), are well-characterized growth factors that are often produced in post-synaptic cells and initiate signals at axon terminals by binding specific Trk receptors [1,2]. How are these signals conveyed to the cell body in order to alter gene expression? Several lines of experiments indicate that transport by microtubule-dependent dynein motors transmit these long-range signals [3][4][5][6]. Although there exist alternative models [4,7,8], it is widely accepted that vesicular-based transport of a "signaling endosome" is required for many, if not most, aspects of retrograde signaling mechanisms and will be the focus of this review.In compartmentalized cultures of sensory and sympathetic neurons, activated phosphorylated Trks (P-Trks) accumulate in cell bodies upon distal axon exposure to neurotrophins [9][10][11]. The signaling endosome model proposes that upon ligand binding and activation, Trk receptors at the distal axon are internalized via clathrin-mediated [12][13][14] or pincher-dependent endocytosis [15,16]. The resultant vesicles containing the ligand-receptor complex are retrogradely transported to the cell body in order to mediate a survival response [3,[7][8][9][10][11]17, 18]. © 2008 Elsevier Ltd. All rights reserved.Corresponding author: Rosalind Segal (E-mail: rosalind_segal@dfci.harvard.edu), Phone (617) 632-4737; Fax (617) 632-2085. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered ...

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“…Tbce, which encodes a tubulin cofactor necessary for proper microtubule assembly, results specifically in motoneuron degeneration and apoptosis when mutated [35]. Mutations in Dync1h1, the dynein heavy chain 1 gene, affect retrograde transport and lead to sensory and/or motor neuron disease, depending on the allele [36,37]. Finally, the dysfunction of two endosome-associated genes, Fig4 and Vps54, causes neuropathy in mouse models.…”

Section: Gene Discovery and Functional Analysismentioning

confidence: 99%

“…2c) to the cytoplasmic dynein heavy chain 1 gene (Dync1h1 prompted a second look at two previously described ENU-induced mutations in Dync1h1, legs at odd angles (Loa) and cramping 1 (Cra1). Loa and Cra1 had been shown to cause late-onset motor neuron degeneration [37]. In contrast, Swl has a long history of investigation as a model of early-onset sensory neuropathy, characterized by a reduction in muscle spindles and a loss of DRG neurons.…”

Section: Allelic Seriesmentioning

confidence: 99%

“…Before genome manipulation was an option, spontaneous and mutagenesis-derived mouse mutants provided an avenue for elucidating gene functions and modeling human disease. More recently, large ENU mutagenesis screens have provided mutations such as the Dync1h1 alleles loa and cra1 [37], which have led to a new PNS phenotype-genotype association, and new alleles for previously known PNS genes, most notably Pmp22 [75] and Qk [55], which have furthered the analysis of these genes.…”

Section: Future Directionsmentioning

confidence: 99%

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Mouse Forward Genetics in the Study of the Peripheral Nervous System and Human Peripheral Neuropathy

Douglas

Popko

2008

Neurochem Res

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Forward genetics, the phenotype-driven approach to investigating gene identity and function, has a long history in mouse genetics. Random mutations in the mouse transcend bias about gene function and provide avenues towards unique discoveries. The study of the peripheral nervous system is no exception; from historical strains such as the trembler mouse, which led to the identification of PMP22 as a human disease gene causing multiple forms of peripheral neuropathy, to the more recent identification of the claw paw and sprawling mutations, forward genetics has long been a tool for probing the physiology, pathogenesis, and genetics of the PNS. Even as spontaneous and mutagenized mice continue to enable the identification of novel genes, provide allelic series for detailed functional studies, and generate models useful for clinical research, new methods, such as the piggyBac transposon, are being developed to further harness the power of forward genetics.

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Mutations in Dynein Link Motor Neuron Degeneration to Defects in Retrograde Transport

Cited by 633 publications

References 29 publications

Axon Transport and Neuropathy

Axon Transport and Neuropathy

Action in the axon: generation and transport of signaling endosomes

Mouse Forward Genetics in the Study of the Peripheral Nervous System and Human Peripheral Neuropathy

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