RESEARCH: Drug prevents cell death in ALS in neuronal cells

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Dorfin prevents cell death by reducing mitochondrial

localizing mutant superoxide dismutase 1 in a neuronal

cell model of familial amyotrophic lateral sclerosis.

Takeuchi H, Niwa J, Hishikawa N, Ishigaki S, Tanaka F,

Doyu M, Sobue G.

Department of Neurology, Nagoya University Graduate

School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya

466-8550, Japan.

Abstract Dorfin is a RING-finger type ubiquitin ligase

for mutant superoxide dismutase 1 (SOD1) that enhances

its degradation. Mutant SOD1s cause familial

amyotrophic lateral sclerosis (FALS) through the gain

of unelucidated toxic properties. We previously showed

that the accumulation of mutant SOD1 in the

mitochondria triggered the release of cytochrome c,

followed by the activation of the caspase cascade and

induction of neuronal cell death. In the present

study, therefore, we investigated whether Dorfin can

modulate the level of mutant SOD1 in the mitochondria

and subsequent caspase activation. We showed that

Dorfin significantly reduced the amount of mutant SOD1

in the mitochondria, the release of cytochrome c and

the activation of the following caspase cascade,

thereby preventing eventual neuronal cell death in a

neuronal cell model of FALS. These results suggest

that reducing the accumulation of mutant SOD1 in the

mitochondria may be a new therapeutic strategy for

mutant SOD1-associated FALS, and that Dorfin may play

a significant role in this.

SOURCE: J Neurochem. 2004 Apr;89(1):64-72.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=PubMed & list_uids=1\

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