Loss of DOPA decarboxylase suppresses tau-induced toxicity in a Caenorhabditis elegans model of tau toxicity
Rebecca L. Kow1,2,3, Jeanna M. Wheeler5, Brian C. Kraemer1,2,4,6
1Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, Seattle, Washington; 2Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington; 3Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington; 4Department of Psychiatry and Behavioral Sciences, University of Washington; 5Seattle Institute for Biomedical & Clinical Research, Seattle, Washington; 6Department of Pathology, University of Washington, Seattle, Washington
The microtubule-associated protein tau accumulates into toxic aggregates in multiple neurodegenerative diseases. To aid in identifying genetic modulators of human tau-induced toxicity, we used a Caenorhabditis elegans model in which human tau protein is overexpressed in all C. elegans neurons. This causes significant motor dysfunction, progressive loss of neurons, shortened lifespan, and the accumulation of hyperphosphorylated and insoluble tau protein. We recently identified DOPA decarboxylase (DDC) as a suppressor of tau toxicity in this model. Loss of the C. elegans DDC gene bas-1 ameliorated multiple phenotypes, reducing behavioral deficits and phosphorylation of tau. Other genes in dopamine and serotonin synthesis did not alter tau-induced toxicity on their own but were required for suppression of tau-induced toxicity by loss of bas-1. We are currently screening kinase and phosphatase genes to see if they modulate the suppression of tau toxicity seen with loss of bas-1/DDC in tau transgenic C. elegans. Suppression of tau-induced behavioral deficits by loss of bas-1/DDC was blocked by the loss of protein kinase C homolog tpa-1, AKT homolog akt-1, or MAP kinases jnk-1 and mpk-2. Additionally, loss of calcineurin homologs cnb-1 and tax-6 also blocked suppression of tau-induced toxicity by loss of bas-1/DDC. Our next steps are to continue screening other genes for possible roles in mediating suppression of tau-induced toxicity by loss of bas-1/DDC and to determine whether these mechanisms translate to mammalian systems.
1. Kow RL, Sikkema C, Wheeler JM, Wilkinson CW, Kraemer BC: Dopa Decarboxylase modulates tau toxicity. Biol Psychiatry 83, 438-446.