Abstract
Cytoplasmic dynein is the most important molecular motor driving the movement of a wide range of cargoes towards the minus ends of microtubules. As a molecular motor protein, dynein performs a variety of basic cellular functions including organelle transport and centrosome assembly. In the nervous system, dynein has been demonstrated to be responsible for axonal retrograde transport. Many studies have revealed direct or indirect evidence of dynein in neurodegenerative diseases such as amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. Among them, a number of mutant proteins involved in various neurodegenerative diseases interact with dynein. Axonal transport disruption is presented as a common feature occurring in neurodegenerative diseases. Dynein heavy chain mutant mice also show features of neurodegenerative diseases. Moreover, defects of dynein-dependent processes such as autophagy or clearance of aggregation-prone proteins are found in most of these diseases. Lines of evidence have also shown that dynein is associated with neurodevelopmental diseases. In this review, we focus on dynein involvement in different neurological diseases and discuss potential underlying mechanisms.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Paschal BM, Shpetner HS, Vallee RB. MAP 1C is a microtubule-activated ATPase which translocates microtubules in vitro and has dynein-like properties. J Cell Biol, 1987, 105: 1273–1282
Allan VJ. Cytoplasmic dynein. Biochem Soc Trans, 2011, 39: 1169–1178
Pfister KK, Shah PR, Hummerich H, Russ A, Cotton J, Annuar AA, King SM, Fisher EM. Genetic analysis of the cytoplasmic dynein subunit families. PLoS Genet, 2006, 2: e1
Pfister KK. Dynein cargo gets its groove back. Structure, 2005, 13: 172–173
Moughamian AJ, Holzbaur EL. Dynactin is required for transport initiation from the distal axon. Neuron, 2012, 74: 331–343
Vaughan KT, Vallee RB. Cytoplasmic dynein binds dynactin through a direct interaction between the intermediate chains and p150Glued. J Cell Biol, 1995, 131: 1507–1516
Kobayashi T, Shiroguchi K, Edamatsu M, Toyoshima YY. Microtubule-binding properties of dynactin p150 expedient for dynein motility. Biochem Biophys Res Commun, 2006, 340: 23–28
Culver-Hanlon TL, Lex SA, Stephens AD, Quintyne NJ, King SJ. A microtubule-binding domain in dynactin increases dynein processivity by skating along microtubules. Nat Cell Biol, 2006, 8: 264–270
Heald R, Tournebize R, Habermann A, Karsenti E, Hyman A. Spindle assembly in Xenopus egg extracts: respective roles of centrosomes and microtubule self-organization. J Cell Biol, 1997, 138: 615–628
Karki S, Holzbaur EL. Cytoplasmic dynein and dynactin in cell division and intracellular transport. Curr Opin Cell Biol, 1999, 11: 45–53
Vallee RB, Williams JC, Varma D, Barnhart LE. Dynein: an ancient motor protein involved in multiple modes of transport. J Neurobiol, 2004, 58: 189–200
Kardon JR, Vale RD. Regulators of the cytoplasmic dynein motor. Nat Rev Mol Cell Biol, 2009, 10: 854–865
McKenney RJ, Vershinin M, Kunwar A, Vallee RB, Gross SP. LIS1 and NudE induce a persistent dynein force-producing state. Cell, 2010, 141: 304–314
Chevalier-Larsen E, Holzbaur EL. Axonal transport and neurodegenerative disease. Biochim Biophys Acta, 2006, 1762: 1094–1108
Soo KY, Farg M, Atkin JD. Molecular motor proteins and amyotrophic lateral sclerosis. Int J Mol Sci, 2011, 12: 9057–9082
Rosen DR. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature, 1993, 364: 362
Brown RJ. Amyotrophic lateral sclerosis: recent insights from genetics and transgenic mice. Cell, 1995, 80: 687–692
Turner BJ, Lopes EC, Cheema SS. Inducible superoxide dismutase 1 aggregation in transgenic amyotrophic lateral sclerosis mouse fibroblasts. J Cell Biochem, 2004, 91: 1074–1084
Kieran D, Hafezparast M, Bohnert S, Dick JR, Martin J, Schiavo G, Fisher EM, Greensmith L. A mutation in dynein rescues axonal transport defects and extends the life span of ALS mice. J Cell Biol, 2005, 169: 561–567
Teuchert M, Fischer D, Schwalenstoecker B, Habisch HJ, Bockers TM, Ludolph AC. A dynein mutation attenuates motor neuron degeneration in SOD1(G93A) mice. Exp Neurol, 2006, 198: 271–274
Zhang F, Strom AL, Fukada K, Lee S, Hayward LJ, Zhu H. Interaction between familial amyotrophic lateral sclerosis (ALS)-linked SOD1 mutants and the dynein complex. J Biol Chem, 2007, 282: 16691–16699
El-Kadi AM, Soura V, Hafezparast M. Defective axonal transport in motor neuron disease. J Neurosci Res, 2007, 85: 2557–2566
Banks GT, Fisher EM. Cytoplasmic dynein could be key to understanding neurodegeneration. Genome Biol, 2008, 9: 214
Chen XJ, Levedakou EN, Millen KJ, Wollmann RL, Soliven B, Popko B. Proprioceptive sensory neuropathy in mice with a mutation in the cytoplasmic Dynein heavy chain 1 gene. J Neurosci, 2007, 27: 14515–14524
Vande VC, Miller TM, Cashman NR, Cleveland DW. Selective association of misfolded ALS-linked mutant SOD1 with the cytoplasmic face of mitochondria. Proc Natl Acad Sci USA, 2008, 105: 4022–4027
Strom AL, Gal J, Shi P, Kasarskis EJ, Hayward LJ, Zhu H. Retrograde axonal transport and motor neuron disease. J Neurochem, 2008, 106: 495–505
Skre H. Genetic and clinical aspects of Charcot-Marie-Tooth’s disease. Clin Genet, 1974, 6: 98–118
Pareyson D, Scaioli V, Laura M. Clinical and electrophysiological aspects of Charcot-Marie-Tooth disease. Neuromolecular Med, 2006, 8: 3–22
Szigeti K, Lupski JR. Charcot-Marie-Tooth disease. Eur J Hum Genet, 2009, 17: 703–710
Weedon MN, Hastings R, Caswell R, Xie W, Paszkiewicz K, Antoniadi T, Williams M, King C, Greenhalgh L, Newbury-Ecob R, Ellard S. Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease. Am J Hum Genet, 2011, 89: 308–312
Verhoeven K, De Jonghe P, Coen K, Verpoorten N, Auer-Grumbach M, Kwon JM, FitzPatrick D, Schmedding E, De Vriendt E, Jacobs A, Van Gerwen V, Wagner K, Hartung HP, Timmerman V. Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy. Am J Hum Genet, 2003, 72: 722–727
Jordens I, Fernandez-Borja M, Marsman M, Dusseljee S, Janssen L, Calafat J, Janssen H, Wubbolts R, Neefjes J. The Rab7 effector protein RILP controls lysosomal transport by inducing the recruitment of dynein-dynactin motors. Curr Biol, 2001, 11: 1680–1685
Perez-Olle R, Jones ST, Liem RK. Phenotypic analysis of neurofilament light gene mutations linked to Charcot-Marie-Tooth disease in cell culture models. Hum Mol Genet, 2004, 13: 2207–2220
Misko A, Jiang S, Wegorzewska I, Milbrandt J, Baloh RH. Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro/Milton complex. J Neurosci, 2010, 30: 4232–4240
Brownlees J, Ackerley S, Grierson AJ, Jacobsen NJ, Shea K, Anderton BH, Leigh PN, Shaw CE, Miller CC. Charcot-Marie-Tooth disease neurofilament mutations disrupt neurofilament assembly and axonal transport. Hum Mol Genet, 2002, 11: 2837–2844
Hafezparast M, Klocke R, Ruhrberg C, Marquardt A, Ahmad-Annuar A, Bowen S, Lalli G, Witherden AS, Hummerich H, Nicholson S, Morgan PJ, Oozageer R, Priestley JV, Averill S, King VR, Ball S, Peters J, Toda T, Yamamoto A, Hiraoka Y, Augustin M, Korthaus D, Wattler S, Wabnitz P, Dickneite C, Lampel S, Boehme F, Peraus G, Popp A, Rudelius M, Schlegel J, Fuchs H, Hrabe DAM, Schiavo G, Shima DT, Russ AP, Stumm G, Martin JE, Fisher EM. Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science, 2003, 300: 808–812
Wiggins LM, Kuta A, Stevens JC, Fisher EM, von Bartheld CS. A novel phenotype for the dynein heavy chain mutation Loa: altered dendritic morphology, organelle density, and reduced numbers of trigeminal motoneurons. J Comp Neurol, 2012, 520: 2757–2773
Zhang Z, Casey DM, Julien JP, Xu Z. Normal dendritic arborization in spinal motoneurons requires neurofilament subunit L. J Comp Neurol, 2002, 450: 144–152
Matsuo S, Ichikawa H, Silos-Santiago I, Arends JJ, Henderson TA, Kiyomiya K, Kurebe M, Jacquin MF. Proprioceptive afferents survive in the masseter muscle of trkC knockout mice. Neuroscience, 2000, 95: 209–216
Ding J, Allen E, Wang W, Valle A, Wu C, Nardine T, Cui B, Yi J, Taylor A, Jeon NL, Chu S, So Y, Vogel H, Tolwani R, Mobley W, Yang Y. Gene targeting of GAN in mouse causes a toxic accumulation of microtubule-associated protein 8 and impaired retrograde axonal transport. Hum Mol Genet, 2006, 15: 1451–463
Lopez-de-Ipina K, Alonso JB, Travieso CM, Sole-Casals J, Egiraun H, Faundez-Zanuy M, Ezeiza A, Barroso N, Ecay-Torres M, Martinez-Lage P, Martinez DLU. On the selection of non-invasive methods based on speech analysis oriented to automatic Alzheimer disease diagnosis. Sensors (Basel), 2013, 13: 6730–6745
Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J. The importance of neuritic plaques and tangles to the development and evolution of AD. Neurology, 2004, 62: 1984–1989
Pigino G, Morfini G, Pelsman A, Mattson MP, Brady ST, Busciglio J. Alzheimer’s presenilin 1 mutations impair kinesin-based axonal transport. J Neurosci, 2003, 23: 4499–4508
Pigino G, Morfini G, Atagi Y, Deshpande A, Yu C, Jungbauer L, LaDu M, Busciglio J, Brady S. Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta. Proc Natl Acad Sci USA, 2009, 106: 5907–5912
Eschbach J, Dupuis L. Cytoplasmic dynein in neurodegeneration. Pharmacol Ther, 2011, 130: 348–363
Kimura N, Imamura O, Ono F, Terao K. Aging attenuates dynactindynein interaction: down-regulation of dynein causes accumulation of endogenous tau and amyloid precursor protein in human neuroblastoma cells. J Neurosci Res, 2007, 85: 2909–2916
Grbovic OM, Mathews PM, Jiang Y, Schmidt SD, Dinakar R, Summers-Terio NB, Ceresa BP, Nixon RA, Cataldo AM. Rab5-stimulated up-regulation of the endocytic pathway increases intracellular betacleaved amyloid precursor protein carboxyl-terminal fragment levels and Abeta production. J Biol Chem, 2003, 278: 31261–31268
Zhao H, Chang R, Che H, Wang J, Yang L, Fang W, Xia Y, Li N, Ma Q, Wang X. Hyperphosphorylation of tau protein by calpain regulation in retina of Alzheimer’s disease transgenic mouse. Neurosci Lett, 2013, 551: 12–16
Geekiyanage H, Upadhye A, Chan C. Inhibition of serine palmitoyltransferase reduces Abeta and tau hyperphosphorylation in a murine model: a safe therapeutic strategy for Alzheimer’s disease. Neurobiol Aging, 2013, 34: 2037–2051
Niewiadomska G, Baksalerska-Pazera M, Riedel G. Altered cellular distribution of phospho-tau proteins coincides with impaired retrograde axonal transport in neurons of aged rats. Ann N Y Acad Sci, 2005, 1048: 287–295
Petersen A, Larsen KE, Behr GG, Romero N, Przedborski S, Brundin P, Sulzer D. Expanded CAG repeats in exon 1 of the Huntington’s disease gene stimulate dopamine-mediated striatal neuron autophagy and degeneration. Hum Mol Genet, 2001, 10: 1243–1254
Farrer MJ, Hulihan MM, Kachergus JM, Dachsel JC, Stoessl AJ, Grantier LL, Calne S, Calne DB, Lechevalier B, Chapon F, Tsuboi Y, Yamada T, Gutmann L, Elibol B, Bhatia KP, Wider C, Vilarino-Guell C, Ross OA, Brown LA, Castanedes-Casey M, Dickson DW, Wszolek ZK. DCTN1 mutations in Perry syndrome. Nat Genet, 2009, 41: 163–165
McKenney RJ, Vershinin M, Kunwar A, Vallee RB, Gross SP. LIS1 and NudE induce a persistent dynein force-producing state. Cell, 2010, 141: 304–314
Grabham PW, Seale GE, Bennecib M, Goldberg DJ, Vallee RB. Cytoplasmic dynein and LIS1 are required for microtubule advance during growth cone remodeling and fast axonal outgrowth. J Neurosci, 2007, 27: 5823–5834
Sasaki S, Shionoya A, Ishida M, Gambello MJ, Yingling J, Wynshaw-Boris A, Hirotsune S. A LIS1/NUDEL/cytoplasmic dynein heavy chain complex in the developing and adult nervous system. Neuron, 2000, 28: 681–696
Shu T, Ayala R, Nguyen MD, Xie Z, Gleeson JG, Tsai LH. Ndel1 operates in a common pathway with LIS1 and cytoplasmic dynein to regulate cortical neuronal positioning. Neuron, 2004, 44: 263–277
Shu T, Ayala R, Nguyen MD, Xie Z, Gleeson JG, Tsai LH. Ndel1 operates in a common pathway with LIS1 and cytoplasmic dynein to regulate cortical neuronal positioning. Neuron, 2004, 44: 263–277
Moon HM, Wynshaw-Boris A. Cytoskeleton in action: lissencephaly, a neuronal migration disorder. Wiley Interdiscip Rev Dev Biol, 2013, 2: 229–245
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is published with open access at springerlink.fh-diploma.de
Contributed equally to this work
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
About this article
Cite this article
Chen, XJ., Xu, H., Cooper, H.M. et al. Cytoplasmic dynein: a key player in neurodegenerative and neurodevelopmental diseases. Sci. China Life Sci. 57, 372–377 (2014). https://doi.org/10.1007/s11427-014-4639-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11427-014-4639-9