An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria

Philip C. Wong, Carlos A. Pardo, David R. Borchelt, Michael K. Lee, Neal G. Copeland, Nancy A. Jenkins, Sangram S. Sisodia, Don W. Cleveland, Donald L. Price

Research output: Contribution to journalArticlepeer-review

1269 Scopus citations


Mutations in Cu/Zn superoxide dismutase (SOD1) cause a subset of cases of familial amyotrophic lateral sclerosis. Four linesof mice accumulating oneof these mutant proteins (G37R) develop severe, progressive motor neuron disease. At lower levels of mutant accumulation, pathology is restricted to lower motor neurons, whereas higher levels cause more severe abnormalities and affect a variety of other neuronal populations. The most obvious cellular abnormality is the presence in axons and dendrites of membrane-bounded vacuoles, which appear to be derived from degenerating mitochondria. Since multiple lines of mice expressing wild-type human SOD1 at similar and higher levels do not show disease, the disease in mice expressing the G37R mutant SOD1 must arise from the acquisition of an adverse property by the mutant enzyme, rather than elevation or loss of SOD1 activity.

Original languageEnglish (US)
Pages (from-to)1105-1116
Number of pages12
Issue number6
StatePublished - Jun 1995

Bibliographical note

Funding Information:
We thank Drs. John W. Griffin and Jeffrey Rothstein for their scientific advice and helpful discussions throughout the course of this work. We thank Dr, Yoram Groner for providing the pHGSOD-SVneo plasmid, Dr. Jonathan Glass for assistance in electromyogral?.hy studies, and Dr. Mike Guarnieri, Ms. Hilda Slunt, and Mr. Hua Chen for their support in the molecular biological analysis. We thank Ms. Venette Nehus, Mr. Frank Barksdale, Ms. Eleanor Brown, bls. Marilyn Peper, Ms. Victoria Gonzalez, and Ms. Gloria Crisostomo for their technical support of histological and ultrastructural methoCs, and Ms. Deborah A. Swing and Ms. Bryn Eagleson for generating ~he transgenic mice. This work has been supported by grants from the United States Public Health Service (AG 05146 and NS 20471), as well as the Amyotrophic Lateral Sclerosis Association. Drs. Cleveland and Price are the recipients of Javits Neuroscience Investigator Awards (NS 27036 and NS 10580, respectively). Drs. Copeland and Jenkins are funded by the National Cancer Institute under contract N01 CO 4600 with ABE The costs of publication of this article were defrayed in part by the payment of page charges. This adicle must therefore be hereby marked "advertisement" in accordance with 18 USC Section 1734 solely to indicate this fact.


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