Journal ArticleDOI
Mutations in Dynein Link Motor Neuron Degeneration to Defects in Retrograde Transport
Majid Hafezparast,Rainer Klocke,Christiana Ruhrberg,Andreas Marquardt,Azlina Ahmad-Annuar,Samantha Bowen,Giovanna Lalli,Abi S. Witherden,Holger Hummerich,Sharon E. Nicholson,P. Jeffrey Morgan,Ravi Oozageer,John V. Priestley,Sharon Averill,V.R. King,Simon T. Ball,Jo Peters,Takashi Toda,Ayumu Yamamoto,Yasushi Hiraoka,Martin Augustin,Dirk Korthaus,Sigrid Wattler,Philipp Wabnitz,Carmen Dickneite,Stefan Lampel,Florian Boehme,Gisela Peraus,Andreas Popp,Martina Rudelius,Juergen Schlegel,Helmut Fuchs,Martin Hrabé de Angelis,Giampietro Schiavo,David T. Shima,Andreas Russ,Gabriele Stumm,Joanne E. Martin,Elizabeth M. C. Fisher +38 more
TLDR
It is shown that missense point mutations in the cytoplasmic dynein heavy chain result in progressive motor neuron degeneration in heterozygous mice, and in homozygotes this is accompanied by the formation of Lewy-like inclusion bodies, thus resembling key features of human pathology.Abstract:
Degenerative disorders of motor neurons include a range of progressive fatal diseases such as amyotrophic lateral sclerosis (ALS), spinal-bulbar muscular atrophy (SBMA), and spinal muscular atrophy (SMA). Although the causative genetic alterations are known for some cases, the molecular basis of many SMA and SBMA-like syndromes and most ALS cases is unknown. Here we show that missense point mutations in the cytoplasmic dynein heavy chain result in progressive motor neuron degeneration in heterozygous mice, and in homozygotes this is accompanied by the formation of Lewy-like inclusion bodies, thus resembling key features of human pathology. These mutations exclusively perturb neuron-specific functions of dynein.read more
Citations
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The roles of intracellular protein-degradation pathways in neurodegeneration
TL;DR: Improving macroautophagy with drugs such as rapamycin could offer a tractable therapeutic strategy for a number of late-onset neurodegenerative diseases.
Journal ArticleDOI
Regulation of Mammalian Autophagy in Physiology and Pathophysiology
Brinda Ravikumar,Sovan Sarkar,Janet E. Davies,Marie Futter,Moisés García-Arencibia,Zeyn W. Green-Thompson,Maria Jimenez-Sanchez,Viktor I. Korolchuk,Maike Lichtenberg,Shouqing Luo,Dunecan Massey,Fiona M. Menzies,Kevin Moreau,Usha Narayanan,Maurizio Renna,Farah H. Siddiqi,Benjamin R. Underwood,Ashley R. Winslow,David C. Rubinsztein +18 more
TL;DR: This review focuses on mammalian autophagy, and an overview of the understanding of its machinery and the signaling cascades that regulate it is given, and the possibility of autophagic upregulation as a therapeutic approach for various conditions is considered.
Journal ArticleDOI
Unraveling the mechanisms involved in motor neuron degeneration in ALS.
TL;DR: Along with errors in the handling of synaptic glutamate and the potential excitotoxic response this provokes, model systems highlight the involvement of nonneuronal cells in disease progression and provide new therapeutic strategies.
Journal ArticleDOI
Decapping and Decay of Messenger RNA Occur in Cytoplasmic Processing Bodies
Ujwal Sheth,Roy Parker +1 more
TL;DR: The flux of mRNAs between polysomes and P bodies is defined as a critical aspect of cytoplasmic mRNA metabolism and a possible site for regulation of mRNA degradation.
Journal ArticleDOI
Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man.
Lindsey R. Fischer,Deborah G. Culver,Philip Tennant,Albert A. Davis,Minsheng Wang,Amilcar A. Castellano-Sanchez,Jaffar M. Khan,Meraida Polak,Jonathan D. Glass +8 more
TL;DR: It is concluded that in this widely studied animal model of human ALS, and in this single human case, motor neuron pathology begins at the distal axon and proceeds in a "dying back" pattern.
References
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Journal ArticleDOI
Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation.
Mark E. Gurney,Haifeng Pu,Arlene Y. Chiu,Mauro C. Dal Canto,Cynthia Y. Polchow,Denise D. Alexander,Jan Caliendo,Afif Hentati,Young W. Kwon,Han Xiang Deng,W. Chen,Ping Zhai,Robert L. Sufit,Teepu Siddique +13 more
TL;DR: In this article, the authors found that mutations of human Cu,Zn superoxide dismutase (SOD) contribute to the pathogenesis of familial amyotrophic lateral sclerosis (ALS).
Journal ArticleDOI
Identification and characterization of a spinal muscular atrophy-determining gene
Suzie Lefebvre,Lydie Burglen,Sophie Reboullet,Olivier Clermont,Philippe Burlet,Louis Viollet,Bernard Bénichou,Corinne Cruaud,Philippe Millasseau,Massimo Zeviani,Denis Le Paslier,Jean Frézal,Daniel Cohen,Jean Weissenbach,Arnold Munnich,Judith Melki +15 more
TL;DR: The inverted duplication of a 500 kb element in normal chromosomes is described and the critical region is narrowed to 140 kb within the telomeric region, suggesting that this gene, termed the survival motor neuron (SMN) gene, is an SMA-determining gene.
Journal ArticleDOI
Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy.
TL;DR: It is concluded that enlargement of the CAG repeat in the androgen receptor gene is probably the cause of X-LINKED spinal and bulbar muscular atrophy.
Journal ArticleDOI
From charcot to lou gehrig: deciphering selective motor neuron death in als
TL;DR: Insights into abnormalities in two genes, together with errors in the handling of synaptic glutamate and the potential excitotoxic response that this alteration provokes, have provided leads for the development of new strategies to identify an as yet elusive remedy for this progressive, fatal disorder.
Journal ArticleDOI
Mutant dynactin in motor neuron disease.
Imke Puls,Catherine Jonnakuty,Bernadette H. LaMonte,Erika L.F. Holzbaur,Mariko Tokito,Eric A. Mann,Mary Kay Floeter,Kimberly Bidus,Dennis Drayna,Shin J. Oh,Robert H. Brown,Christy L. Ludlow,Kenneth H. Fischbeck +12 more
TL;DR: The results show that dysfunction of dynactin-mediated transport can lead to human motor neuron disease.