Genetics, Vol. 165, 1233-1242, November 2003, Copyright © 2003

Genetic Modifiers of Tauopathy in Drosophila

Joshua M. Shulmana and Mel B. Feanya
a Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115

Corresponding author: Mel B. Feany, Brigham and Women's Hospital, 221 Longwood Ave., Room 514, Boston, MA 02115., mel_feany{at}hms.harvard.edu (E-mail)

Communicating editor: K. ANDERSON

In Alzheimer's disease and related disorders, the microtubule-associated protein Tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles. Mutations in the tau gene cause familial frontotemporal dementia. To investigate the molecular mechanisms responsible for Tau-induced neurodegeneration, we conducted a genetic modifier screen in a Drosophila model of tauopathy. Kinases and phosphatases comprised the major class of modifiers recovered, and several candidate Tau kinases were similarly shown to enhance Tau toxicity in vivo. Despite some clinical and pathological similarities among neurodegenerative disorders, a direct comparison of modifiers between different Drosophila disease models revealed that the genetic pathways controlling Tau and polyglutamine toxicity are largely distinct. Our results demonstrate that kinases and phosphatases control Tau-induced neurodegeneration and have important implications for the development of therapies in Alzheimer's disease and related disorders.




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