HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 36, 24972-24981, September 5, 2008

This Article Free via Author's Choice: AC AC Full Text Full Text (PDF) Author Profile AC All Versions of this Article: 283/36/24972    most recent M804817200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Watson, M. R. Articles by Bonini, N. M. Search for Related Content PubMed PubMed Citation Articles by Watson, M. R. Articles by Bonini, N. M. Related Collections Papers Of The Week Social Bookmarking                      What's this?

A Drosophila Model for Amyotrophic Lateral Sclerosis Reveals Motor Neuron Damage by Human SOD1^*

Melanie R. Watson, Robert D. Lagow, Kexiang Xu^¶, Bing Zhang, and Nancy M. Bonini^¶||1

From the ^¶Department of Biology, University of Pennsylvania, the Department of Neuroscience, University of Pennsylvania School of Medicine, and the ^||Howard Hughes Medical Institute, Philadelphia, Pennsylvania 19104 and the Department of Zoology, University of Oklahoma, Norman, Oklahoma 73019

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that leads to loss of motor function and early death. About 5% of cases are inherited, with the majority of identified linkages in the gene encoding copper, zinc-superoxide dismutase (SOD1). Strong evidence indicates that the SOD1 mutations confer dominant toxicity on the protein. To provide new insight into mechanisms of ALS, we have generated and characterized a model for familial ALS in Drosophila with transgenic expression of human SOD1. Expression of wild type or disease-linked (A4V, G85R) mutants of human SOD1 selectively in motor neurons induced progressive climbing deficits. These effects were accompanied by defective neural circuit electrophysiology, focal accumulation of human SOD1 protein in motor neurons, and a stress response in surrounding glia. However, toxicity was not associated with oligomerization of SOD1 and did not lead to neuronal loss. These studies uncover cell-autonomous injury by SOD1 to motor neurons in vivo, as well as non-autonomous effects on glia, and provide the foundation for new insight into injury and protection of motor neurons in ALS.

Received for publication, June 24, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grant AG09215 from the NIA (to N. M. B.) and National Institutes of Health Grant ES014441 from the NIEHS (to B. Z.). This work was also supported by the Systems and Integrated Biology Training Grant and the Developmental Biology Training Grant (to M. R. W.) and a grant from the David and Lucile Packard Foundation (to N. M. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This article was selected as a Paper of the Week.

Author's Choice—Final version full access.

Author's Choice

Creative Commons Attribution Non-Commercial License applies to Author Choice Articles

¹ An Investigator of the Howard Hughes Medical Institute. To whom correspondence should be addressed: Dept Biology, 306 Leidy Laboratory, University of Pennsylvania, Howard Hughes Medical Institute, Philadelphia, PA 19104-6018. Tel.: 215-573-9267; Fax: 215-573-5754; E-mail: nbonini{at}sas.upenn.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?