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First published on September 28, 2006; DOI: 10.1124/mol.106.028415

0026-895X/07/7101-30-37$20.00
Mol Pharmacol 71:30-37, 2007

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Pyrrolidine Dithiocarbamate Inhibits Induction of Immunoproteasome and Decreases Survival in a Rat Model of Amyotrophic Lateral Sclerosis

Toni Ahtoniemi, Gundars Goldsteins, Velta Keksa-Goldsteine, Tarja Malm, Katja Kanninen, Antero Salminen, and Jari Koistinaho

Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences (T.A., G.G., V.K.-G., T.M., K.K., J.K.), Department of Neuroscience and Neurology (A.S.), University of Kuopio, and Department of Oncology (J.K.), Kuopio University Hospital, Kuopio, Finland

Pyrrolidine dithiocarbamate (PDTC), an inhibitor of nuclear transcription factor {kappa}-B (NF-{kappa}B) and an antioxidant, has beneficial effects in animal models of various diseases, including arthritis, brain ischemia, spinal cord injury, Alzheimer's disease, and Duchenne muscular dystrophy. Because inflammation and oxidative damage are also hallmarks of amyotrophic lateral sclerosis (ALS), we studied the effect of oral PDTC treatment on G93A-superoxide dismutase 1 (SOD1) transgenic (TG) rat model of human ALS and observed that PDTC treatment significantly decreases the survival. PDTC treatment evoked the end stage of the disease at 121 ± 21 days, whereas untreated TG animals reached the end stage at 141 ± 13 days (p < 0.01). The DNA binding activity of NF-{kappa}B was not altered in G93A-SOD1 TG rats by PDTC treatment. The copper concentration in the spinal cord was increased after PDTC treatment both in G93A-SOD1 TG and wild-type rats, suggesting that increased copper may enhance the neurotoxicity of mutant SOD1. The amount of ubiquitinated proteins were significantly higher and proteasomal activity was decreased in the spinal cords of PDTC-treated TG rats compared with other groups, suggesting that PDTC treatment decreases proteasome function. Immunoblotting and immunocytochemistry showed that the level of immunoproteasome but not constitutive proteasome was increased in glia of G93A-SOD1 TG rats along with disease development. PDTC treatment completely blocked the induction of immunoproteasome expression without affecting constitutive proteasome. These results suggest that PDTC acts as an immunoproteasome inhibitor in mutant SOD1 rats and that immunoproteasome may help the nervous system to cope with deleterious effects of SOD1-G93A mutation.

Received June 29, 2006; accepted September 27, 2006

Address correspondence to: Dr. Jari Koistinaho, Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, P.O.B. 1627, FIN-70211 Kuopio, Finland. E-mail: jari.koistinaho{at}uku.fi






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