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PNAS 100 (16): 9578-9583

Copyright © 2003 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / NEUROSCIENCE

Stimulation of NeuroD activity by huntingtin and huntingtin-associated proteins HAP1 and MLK2

Edoardo Marcora, Katherine Gowan, and Jacqueline E. Lee{dagger}

Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Campus Box 347, Boulder, CO 80309

Received for publication April 10, 2003.

Abstract: NeuroD (ND) is a basic helix–loop–helix transcription factor important for neuronal development and survival. By using a yeast two-hybrid screen, we identified two proteins that interact with ND, huntingtin-associated protein 1 (HAP1) and mixed-lineage kinase 2 (MLK2), both of which are known to interact with huntingtin (Htt). Htt is a ubiquitous protein important for neuronal transcription, development, and survival, and loss of its function has been implicated in the pathogenesis of Huntington's disease, a neurodegenerative disorder. However, the mechanism by which Htt exerts its neuron-specific function at the molecular level is unknown. Here we report that Htt interacts with ND via HAP1, and that MLK2 phosphorylates and stimulates the activity of ND. Furthermore, we show that Htt and HAP1 facilitate the activation of ND by MLK2. To our knowledge, ND is the first example of a neuron-specific transcription factor involved in neuronal development and survival whose activity is modulated by Htt. We propose that Htt, together with HAP1, may function as a scaffold for the activation of ND by MLK2.

{dagger} To whom correspondence should be addressed. E-mail: Jackie.Lee{at}colorado.edu.

Communicated by William B. Wood, University of Colorado, Boulder, CO, June 3, 2003

Abbreviations: Htt, huntington; bHLH, basic helix–loop–helix; HAP1, Htt-associated protein 1; HD, Huntington's disease; MLK2, mixed-lineage kinase 2; HA, hemagglutinin; MT, Myc-tagged; ND, NeuroD; LZ, leucine zipper.

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