Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 2 June 2006:
Vol. 312. no. 5778, pp. 1389 - 1392
DOI: 10.1126/science.1123511
Prev | Table of Contents | Next

Reports

Onset and Progression in Inherited ALS Determined by Motor Neurons and Microglia

Séverine Boillée,1* Koji Yamanaka,1*{dagger} Christian S. Lobsiger,1 Neal G. Copeland,2 Nancy A. Jenkins,2 George Kassiotis,3{ddagger} George Kollias,3 Don W. Cleveland1{dagger}

Dominant mutations in superoxide dismutase cause amyotrophic lateral sclerosis (ALS), a progressive paralytic disease characterized by loss of motor neurons. With the use of mice carrying a deletable mutant gene, expression within motor neurons was shown to be a primary determinant of disease onset and of an early phase of disease progression. Diminishing the mutant levels in microglia had little effect on the early disease phase but sharply slowed later disease progression. Onset and progression thus represent distinct disease phases defined by mutant action within different cell types to generate non–cell-autonomous killing of motor neurons; these findings validate therapies, including cell replacement, targeted to the non-neuronal cells.

1 Ludwig Institute for Cancer Research and Departments of Medicine and Neuroscience, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
2 Mouse Cancer Genetics Program, National Cancer Institute–Frederick Cancer Research and Development Center, Frederick, MD 21702, USA.
3 Institute of Immunology, Biomedical Sciences Research Center Alexander Fleming, 166 72 Vari, Greece.

* These authors contributed equally to this work.

{ddagger} Present address: Division of Immunoregulation, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.

{dagger} To whom correspondence should be addressed. E-mail: dcleveland{at}ucsd.edu (D.W.C.); kyamanaka{at}ucsd.edu (K.Y.)

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
The Proinflammatory Action of Microglial P2 Receptors Is Enhanced in SOD1 Models for Amyotrophic Lateral Sclerosis.
N. D'Ambrosi, P. Finocchi, S. Apolloni, M. Cozzolino, A. Ferri, V. Padovano, G. Pietrini, M. T. Carri, and C. Volonte (2009)
J. Immunol. 183, 4648-4656
   Abstract »    Full Text »    PDF »
Review: Evidence-based drug treatment in amyotrophic lateral sclerosis and upcoming clinical trials.
A. C. Ludolph and S. Jesse (2009)
Therapeutic Advances in Neurological Disorders 2, 319-326
   Abstract »    PDF »
A Switch in Retrograde Signaling from Survival to Stress in Rapid-Onset Neurodegeneration.
E. Perlson, G.-B. Jeong, J. L. Ross, R. Dixit, K. E. Wallace, R. G. Kalb, and E. L. F. Holzbaur (2009)
J. Neurosci. 29, 9903-9917
   Abstract »    Full Text »    PDF »
Direct Magnetic Resonance Evidence for Peroxymonocarbonate Involvement in the Cu,Zn-Superoxide Dismutase Peroxidase Catalytic Cycle.
M. G. Bonini, S. A. Gabel, K. Ranguelova, K. Stadler, E. F. DeRose, R. E. London, and R. P. Mason (2009)
J. Biol. Chem. 284, 14618-14627
   Abstract »    Full Text »    PDF »
Progressive polyuria without vasopressin neuron loss in a mouse model for familial neurohypophysial diabetes insipidus.
M. Hayashi, H. Arima, N. Ozaki, Y. Morishita, M. Hiroi, N. Ozaki, H. Nagasaki, N. Kinoshita, M. Ueda, A. Shiota, et al. (2009)
Am J Physiol Regulatory Integrative Comp Physiol 296, R1641-R1649
   Abstract »    Full Text »    PDF »
Potentiation of Amyotrophic Lateral Sclerosis (ALS)-associated TDP-43 Aggregation by the Proteasome-targeting Factor, Ubiquilin 1.
S. H. Kim, Y. Shi, K. A. Hanson, L. M. Williams, R. Sakasai, M. J. Bowler, and R. S. Tibbetts (2009)
J. Biol. Chem. 284, 8083-8092
   Abstract »    Full Text »    PDF »
Schwann cells expressing dismutase active mutant SOD1 unexpectedly slow disease progression in ALS mice.
C. S. Lobsiger, S. Boillee, M. McAlonis-Downes, A. M. Khan, M. L. Feltri, K. Yamanaka, and D. W. Cleveland (2009)
PNAS 106, 4465-4470
   Abstract »    Full Text »    PDF »
Human embryonic stem cell-derived motor neurons expressing SOD1 mutants exhibit typical signs of motor neuron degeneration linked to ALS.
S. Karumbayaram, T. K. Kelly, A. A. Paucar, A. J. T. Roe, J. A. Umbach, A. Charles, S. A. Goldman, H. I. Kornblum, and M. Wiedau-Pazos (2009)
Dis. Model. Mech. 2, 189-195
   Abstract »    Full Text »    PDF »
Mutations in FUS, an RNA Processing Protein, Cause Familial Amyotrophic Lateral Sclerosis Type 6.
C. Vance, B. Rogelj, T. Hortobagyi, K. J. De Vos, A. L. Nishimura, J. Sreedharan, X. Hu, B. Smith, D. Ruddy, P. Wright, et al. (2009)
Science 323, 1208-1211
   Abstract »    Full Text »    PDF »
Expression of Amyotrophic Lateral Sclerosis-linked SOD1 Mutant Increases the Neurotoxic Potential of Microglia via TLR2.
Y. Liu, W. Hao, A. Dawson, S. Liu, and K. Fassbender (2009)
J. Biol. Chem. 284, 3691-3699
   Abstract »    Full Text »    PDF »
A CSF biomarker panel for identification of patients with amyotrophic lateral sclerosis.
R. M. Mitchell, W. M. Freeman, W. T. Randazzo, H. E. Stephens, J. L. Beard, Z. Simmons, and J. R. Connor (2009)
Neurology 72, 14-19
   Abstract »    Full Text »    PDF »
Nrf2 Activation in Astrocytes Protects against Neurodegeneration in Mouse Models of Familial Amyotrophic Lateral Sclerosis.
M. R. Vargas, D. A. Johnson, D. W. Sirkis, A. Messing, and J. A. Johnson (2008)
J. Neurosci. 28, 13574-13581
   Abstract »    Full Text »    PDF »
Granulocyte-colony stimulating factor improves outcome in a mouse model of amyotrophic lateral sclerosis.
C. Pitzer, C. Kruger, C. Plaas, F. Kirsch, T. Dittgen, R. Muller, R. Laage, S. Kastner, S. Suess, R. Spoelgen, et al. (2008)
Brain 131, 3335-3347
   Abstract »    Full Text »    PDF »
T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS.
I. M. Chiu, A. Chen, Y. Zheng, B. Kosaras, S. A. Tsiftsoglou, T. K. Vartanian, R. H. Brown Jr, and M. C. Carroll (2008)
PNAS 105, 17913-17918
   Abstract »    Full Text »    PDF »
G-Protein-Coupled Receptor Screen Reveals a Role for Chemokine Receptor CCR5 in Suppressing Microglial Neurotoxicity.
K. Gamo, S. Kiryu-Seo, H. Konishi, S. Aoki, K. Matsushima, K. Wada, and H. Kiyama (2008)
J. Neurosci. 28, 11980-11988
   Abstract »    Full Text »    PDF »
Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase.
C. Cheret, A. Gervais, A. Lelli, C. Colin, L. Amar, P. Ravassard, J. Mallet, A. Cumano, K.-H. Krause, and M. Mallat (2008)
J. Neurosci. 28, 12039-12051
   Abstract »    Full Text »    PDF »
Neonatal Neuronal Circuitry Shows Hyperexcitable Disturbance in a Mouse Model of the Adult-Onset Neurodegenerative Disease Amyotrophic Lateral Sclerosis.
B. van Zundert, M. H. Peuscher, M. Hynynen, A. Chen, R. L. Neve, R. H. Brown Jr, M. Constantine-Paton, and M. C. Bellingham (2008)
J. Neurosci. 28, 10864-10874
   Abstract »    Full Text »    PDF »
Hematopoietic stem cell transplantation in patients with sporadic amyotrophic lateral sclerosis.
S. H. Appel, J. I. Engelhardt, J. S. Henkel, L. Siklos, D. R. Beers, A. A. Yen, E. P. Simpson, Y. Luo, G. Carrum, H. E. Heslop, et al. (2008)
Neurology 71, 1326-1334
   Abstract »    Full Text »    PDF »
Ablation of Proliferating Microglia Does Not Affect Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis Caused by Mutant Superoxide Dismutase.
G. Gowing, T. Philips, B. Van Wijmeersch, J.-N. Audet, M. Dewil, L. Van Den Bosch, A. D. Billiau, W. Robberecht, and J.-P. Julien (2008)
J. Neurosci. 28, 10234-10244
   Abstract »    Full Text »    PDF »
CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS.
D. R. Beers, J. S. Henkel, W. Zhao, J. Wang, and S. H. Appel (2008)
PNAS 105, 15558-15563
   Abstract »    Full Text »    PDF »
A Drosophila Model for Amyotrophic Lateral Sclerosis Reveals Motor Neuron Damage by Human SOD1.
M. R. Watson, R. D. Lagow, K. Xu, B. Zhang, and N. M. Bonini (2008)
J. Biol. Chem. 283, 24972-24981
   Abstract »    Full Text »    PDF »
Complete Loss of Post-translational Modifications Triggers Fibrillar Aggregation of SOD1 in the Familial Form of Amyotrophic Lateral Sclerosis.
Y. Furukawa, K. Kaneko, K. Yamanaka, T. V. O'Halloran, and N. Nukina (2008)
J. Biol. Chem. 283, 24167-24176
   Abstract »    Full Text »    PDF »
Induced Pluripotent Stem Cells Generated from Patients with ALS Can Be Differentiated into Motor Neurons.
J. T. Dimos, K. T. Rodolfa, K. K. Niakan, L. M. Weisenthal, H. Mitsumoto, W. Chung, G. F. Croft, G. Saphier, R. Leibel, R. Goland, et al. (2008)
Science 321, 1218-1221
   Abstract »    Full Text »    PDF »
Mutant dynein (Loa) triggers proprioceptive axon loss that extends survival only in the SOD1 ALS model with highest motor neuron death.
H. S. Ilieva, K. Yamanaka, S. Malkmus, O. Kakinohana, T. Yaksh, M. Marsala, and D. W. Cleveland (2008)
PNAS 105, 12599-12604
   Abstract »    Full Text »    PDF »
Molecular dissection of ALS-associated toxicity of SOD1 in transgenic mice using an exon-fusion approach.
D. Han-Xiang, J. Hujun, F. Ronggen, Z. Hong, S. Yong, L. Erdong, H. Makito, C. D. C. Mauro, and S. Teepu (2008)
Hum. Mol. Genet. 17, 2310-2319
   Abstract »    Full Text »    PDF »
Early oxidative damage underlying neurodegeneration in X-adrenoleukodystrophy.
S. Fourcade, J. Lopez-Erauskin, J. Galino, C. Duval, A. Naudi, M. Jove, S. Kemp, F. Villarroya, I. Ferrer, R. Pamplona, et al. (2008)
Hum. Mol. Genet. 17, 1762-1773
   Abstract »    Full Text »    PDF »
Therapeutic Gene Silencing Delivered by a Chemically Modified Small Interfering RNA against Mutant SOD1 Slows Amyotrophic Lateral Sclerosis Progression.
H. Wang, A. Ghosh, H. Baigude, C.-s. Yang, L. Qiu, X. Xia, H. Zhou, T. M. Rana, and Z. Xu (2008)
J. Biol. Chem. 283, 15845-15852
   Abstract »    Full Text »    PDF »
ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1.
H. Nishitoh, H. Kadowaki, A. Nagai, T. Maruyama, T. Yokota, H. Fukutomi, T. Noguchi, A. Matsuzawa, K. Takeda, and H. Ichijo (2008)
Genes & Dev. 22, 1451-1464
   Abstract »    Full Text »    PDF »
Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice.
K. Yamanaka, S. Boillee, E. A. Roberts, M. L. Garcia, M. McAlonis-Downes, O. R. Mikse, D. W. Cleveland, and L. S. B. Goldstein (2008)
PNAS 105, 7594-7599
   Abstract »    Full Text »    PDF »
Heterodimer formation of wild-type and amyotrophic lateral sclerosis-causing mutant Cu/Zn-superoxide dismutase induces toxicity independent of protein aggregation.
H. Witan, A. Kern, I. Koziollek-Drechsler, R. Wade, C. Behl, and A. M. Clement (2008)
Hum. Mol. Genet. 17, 1373-1385
   Abstract »    Full Text »    PDF »
Diagnosis and management of motor neurone disease.
C. J McDermott and P. J Shaw (2008)
BMJ 336, 658-662
   Full Text »    PDF »
Histone Deacetylase Inhibition Modulates Kynurenine Pathway Activation in Yeast, Microglia, and Mice Expressing a Mutant Huntingtin Fragment.
F. Giorgini, T. Moller, W. Kwan, D. Zwilling, J. L. Wacker, S. Hong, L.-C. L. Tsai, C. S. Cheah, R. Schwarcz, P. Guidetti, et al. (2008)
J. Biol. Chem. 283, 7390-7400
   Abstract »    Full Text »    PDF »
A novel noncoding RNA rescues mutant SOD1-mediated cell death.
Y. Chang, M. P. Stockinger, H. Tashiro, and C.-l. G. Lin (2008)
FASEB J 22, 691-702
   Abstract »    Full Text »    PDF »
Neuron-Specific Expression of Mutant Superoxide Dismutase Is Sufficient to Induce Amyotrophic Lateral Sclerosis in Transgenic Mice.
D. Jaarsma, E. Teuling, E. D. Haasdijk, C. I. De Zeeuw, and C. C. Hoogenraad (2008)
J. Neurosci. 28, 2075-2088
   Abstract »    Full Text »    PDF »
Gene profiling of skeletal muscle in an amyotrophic lateral sclerosis mouse model.
J.-L. Gonzalez de Aguilar, C. Niederhauser-Wiederkehr, B. Halter, M. De Tapia, F. Di Scala, P. Demougin, L. Dupuis, M. Primig, V. Meininger, and J.-P. Loeffler (2008)
Physiol Genomics 32, 207-218
   Abstract »    Full Text »    PDF »
Loss of a Child and the Risk of Amyotrophic Lateral Sclerosis.
F. Fang, W. Ye, K. Fall, M. Lekander, H. Wigzell, P. Sparen, H.-O. Adami, and U. Valdimarsdottir (2008)
Am. J. Epidemiol. 167, 203-210
   Abstract »    Full Text »    PDF »
MyD88-deficient bone marrow cells accelerate onset and reduce survival in a mouse model of amyotrophic lateral sclerosis.
J. Kang and S. Rivest (2007)
J. Cell Biol. 179, 1219-1230
   Abstract »    Full Text »    PDF »
Exogenous Delivery of Heat Shock Protein 70 Increases Lifespan in a Mouse Model of Amyotrophic Lateral Sclerosis.
D. J. Gifondorwa, M. B. Robinson, C. D. Hayes, A. R. Taylor, D. M. Prevette, R. W. Oppenheim, J. Caress, and C. E. Milligan (2007)
J. Neurosci. 27, 13173-13180
   Abstract »    Full Text »    PDF »
A Caspase-3-cleaved Fragment of the Glial Glutamate Transporter EAAT2 Is Sumoylated and Targeted to Promyelocytic Leukemia Nuclear Bodies in Mutant SOD1-linked Amyotrophic Lateral Sclerosis.
S. L. Gibb, W. Boston-Howes, Z. S. Lavina, S. Gustincich, R. H. Brown Jr., P. Pasinelli, and D. Trotti (2007)
J. Biol. Chem. 282, 32480-32490
   Abstract »    Full Text »    PDF »
Murine models of acute neuronopathic Gaucher disease.
I. B. Enquist, C. L. Bianco, A. Ooka, E. Nilsson, J.-E. Mansson, M. Ehinger, J. Richter, R. O. Brady, D. Kirik, and S. Karlsson (2007)
PNAS 104, 17483-17488
   Abstract »    Full Text »    PDF »
Microarray Analysis of the Cellular Pathways Involved in the Adaptation to and Progression of Motor Neuron Injury in the SOD1 G93A Mouse Model of Familial ALS.
L. Ferraiuolo, P. R. Heath, H. Holden, P. Kasher, J. Kirby, and P. J. Shaw (2007)
J. Neurosci. 27, 9201-9219
   Abstract »    Full Text »    PDF »
Increased peripheral lipid clearance in an animal model of amyotrophic lateral sclerosis.
A. Fergani, H. Oudart, J.-L. Gonzalez De Aguilar, B. Fricker, F. Rene, J.-F. Hocquette, V. Meininger, L. Dupuis, and J.-P. Loeffler (2007)
J. Lipid Res. 48, 1571-1580
   Abstract »    Full Text »    PDF »
Tryptophan 32 Potentiates Aggregation and Cytotoxicity of a Copper/Zinc Superoxide Dismutase Mutant Associated with Familial Amyotrophic Lateral Sclerosis.
D. M. Taylor, B. F. Gibbs, E. Kabashi, S. Minotti, H. D. Durham, and J. N. Agar (2007)
J. Biol. Chem. 282, 16329-16335
   Abstract »    Full Text »    PDF »
Sodium Valproate Exerts Neuroprotective Effects In Vivo through CREB-Binding Protein-Dependent Mechanisms But Does Not Improve Survival in an Amyotrophic Lateral Sclerosis Mouse Model.
C. Rouaux, I. Panteleeva, F. Rene, J.-L. Gonzalez de Aguilar, A. Echaniz-Laguna, L. Dupuis, Y. Menger, A.-L. Boutillier, and J.-P. Loeffler (2007)
J. Neurosci. 27, 5535-5545
   Abstract »    Full Text »    PDF »
Neural stem cells LewisX + CXCR4 + modify disease progression in an amyotrophic lateral sclerosis model.
S. Corti, F. Locatelli, D. Papadimitriou, R. Del Bo, M. Nizzardo, M. Nardini, C. Donadoni, S. Salani, F. Fortunato, S. Strazzer, et al. (2007)
Brain 130, 1289-1305
   Abstract »    Full Text »    PDF »
Inaugural Article: Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons.
C. S. Lobsiger, S. Boillee, and D. W. Cleveland (2007)
PNAS 104, 7319-7326
   Abstract »    Full Text »    PDF »
Therapeutic effects of immunization with mutant superoxide dismutase in mice models of amyotrophic lateral sclerosis.
M. Urushitani, S. A. Ezzi, and J.-P. Julien (2007)
PNAS 104, 2495-2500
   Abstract »    Full Text »    PDF »
From the Cover: Gene transfer demonstrates that muscle is not a primary target for non-cell-autonomous toxicity in familial amyotrophic lateral sclerosis.
T. M. Miller, S. H. Kim, K. Yamanaka, M. Hester, P. Umapathi, H. Arnson, L. Rizo, J. R. Mendell, F. H. Gage, D. W. Cleveland, et al. (2006)
PNAS 103, 19546-19551
   Abstract »    Full Text »    PDF »
Absence of Tumor Necrosis Factor-{alpha} Does Not Affect Motor Neuron Disease Caused by Superoxide Dismutase 1 Mutations..
G. Gowing, F. Dequen, G. Soucy, and J.-P. Julien (2006)
J. Neurosci. 26, 11397-11402
   Abstract »    Full Text »    PDF »
Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis.
D. R. Beers, J. S. Henkel, Q. Xiao, W. Zhao, J. Wang, A. A. Yen, L. Siklos, S. R. McKercher, and S. H. Appel (2006)
PNAS 103, 16021-16026
   Abstract »    Full Text »    PDF »
Amyotrophic lateral sclerosis -- are microglia killing motor neurons?.
D. R. Borchelt (2006)
N. Engl. J. Med. 355, 1611-1613
   Full Text »    PDF »
Disease-Modifying Pathways in Neurodegeneration.
S. Finkbeiner, A. Maria Cuervo, R. I. Morimoto, and P. J. Muchowski (2006)
J. Neurosci. 26, 10349-10357
   Full Text »    PDF »
The inflammatory NADPH oxidase enzyme modulates motor neuron degeneration in amyotrophic lateral sclerosis mice.
D.-C. Wu, D. B. Re, M. Nagai, H. Ischiropoulos, and S. Przedborski (2006)
PNAS 103, 12132-12137
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)