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Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis


Dominant mutations in superoxide dismutase cause amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease that is characterized by the loss of motor neurons. Using mice carrying a deletable mutant gene, diminished mutant expression in astrocytes did not affect onset, but delayed microglial activation and sharply slowed later disease progression. These findings demonstrate that mutant astrocytes are viable targets for therapies for slowing the progression of non–cell autonomous killing of motor neurons in ALS.

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Figure 1: Selective Cre-mediated gene excision shows that mutant SOD1 action in astrocytes is a primary determinant of late disease progression.
Figure 2: Selective downregulation of mutant SOD1 in astrocytes significantly inhibits microglial activation.
Figure 3: Mutant-expressing astrocytes enhance microglial activation and induction of iNOS.

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This work was supported by a US National Institutes of Health grant (NS 27036) and a grant from the Packard ALS Center at Johns Hopkins (D.W.C.), as well as a Muscular Dystrophy Association developmental grant, the Uehara Memorial Foundation, the Nakabayashi Trust for ALS Research and a grant-in-aid for Scientific Research (19591021) and on Priority Area (19044048) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (K.Y.). Salary support for D.W.C is provided by the Ludwig Institute for Cancer Research. S.B. is a recipient of a Fondation pour la Recherche Medical fellowship, an Institut National de la santé et de la Recherché Medicale fellowship and a Muscular Dystrophy Association developmental grant.

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K.Y., S.J.C., S.B., N.F.-T. and H.Y. conducted the experiments. D.H.G., R.T. and H.M. provided essential experimental tools and advice. K.Y., S.B., and D.W.C. were responsible for the overall design of the project, analyses of the results and writing the manuscript.

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Correspondence to Koji Yamanaka or Don W Cleveland.

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Yamanaka, K., Chun, S., Boillee, S. et al. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci 11, 251–253 (2008).

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