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The Journal of Neuroscience, February 27, 2008, 28(9):2075-2088; doi:10.1523/JNEUROSCI.5258-07.2008

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Neurobiology of Disease
Neuron-Specific Expression of Mutant Superoxide Dismutase Is Sufficient to Induce Amyotrophic Lateral Sclerosis in Transgenic Mice

Dick Jaarsma,¹ Eva Teuling,¹ Elize D. Haasdijk,¹ Chris I. De Zeeuw,^1,2 and Casper C. Hoogenraad¹

¹Department of Neuroscience, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands, and ²Netherlands Institute for Neuroscience, 1105 BA Amsterdam, The Netherlands

Correspondence should be addressed to either Dick Jaarsma or Casper C. Hoogenraad, Department of Neuroscience, Erasmus Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands. Email: d.jaarsma{at}erasmusmc.nl or Email: c.hoogenraad{at}erasmusmc.nl

Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), an adult-onset progressive paralytic disease characterized by loss of motor neurons, and cause an ALS-like disease when expressed in mice. Recent data have suggested that motor neuron degeneration results from toxic actions of mutant SOD1 operating in both motor neurons and their neighboring glia, raising the question whether mutant SOD1 expression selectively in neurons is sufficient to induce disease. Here we show that neuronal expression of mutant SOD1 is sufficient to cause motor neuron degeneration and paralysis in transgenic mice with cytosolic dendritic ubiquitinated SOD1 aggregates as the dominant pathological feature. In addition, we show that crossing our neuron-specific mutant SOD1 mice with ubiquitously wild-type SOD1-expressing mice leads to dramatic wild-type SOD1 aggregation in oligodendroglia after the onset of neuronal degeneration. Together, our findings support a pathogenic scenario in which mutant SOD1 in neurons triggers neuronal degeneration, which in turn may facilitate aggregate formation in surrounding glial cells.

Key words: amyotrophic lateral sclerosis (ALS); protein aggregation; oligodendrocyte; astrocyte; motor neuron disease; mouse model

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Received Oct. 12, 2007; revised Jan. 7, 2008; accepted Jan. 8, 2008.

Correspondence should be addressed to either Dick Jaarsma or Casper C. Hoogenraad, Department of Neuroscience, Erasmus Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands. Email: d.jaarsma{at}erasmusmc.nl or Email: c.hoogenraad{at}erasmusmc.nl

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