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Human Molecular Genetics Advance Access published online on June 5, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm134
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Published by Oxford University Press 2007

Intersectin Enhances Huntingtin Aggregation and Neurodegeneration Through Activation of c-Jun-NH2-Terminal Kinase (JNK)

Erica Scappini1,2, Tong-Wey Koh3, Negin P. Martin1,2 and John P. O'Bryan1,2,4,*

1 Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA 2 Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA 3 Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA 4 Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA

* Address correspondence to: John P. O'Bryan, Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612: Tel: 312-996-6221; Fax: 312-996-1225; E-mail: obryanj{at}uic.edu

Received March 23, 2007; Revised May 13, 2007; Accepted May 13, 2007

Huntingon's Disease (HD) is a progressive neurodegenerative disease arising from expansion of a polyglutamine (polyQ) tract in the protein huntingtin (Htt) resulting in aggregation of mutant Htt into nuclear and/or cytosolic inclusions in neurons. Mutant Htt affects multiple processes including protein degradation, transcription, signal transduction, fast axonal transport and endocytosis (reviewed in (1)). Here, we report that the endocytic and signal transduction scaffold intersectin (ITSN) increased aggregate formation by mutant Htt through activation of the JNK-MAPK pathway. Conversely, silencing ITSN or inhibiting JNK attenuated aggregate formation. Using a Drosophila model for polyQ repeat disease, we observed that ITSN enhanced polyQ-mediated neurotoxicity. A reciprocal relationship was observed between ITSN and Htt. While ITSN enhanced Htt aggregation and toxicity, Htt, in turn, inhibited the cooperativity between ITSN and the epidermal growth factor receptor signal transduction pathway. Finally, we observed that ITSN overexpression enhanced aggregation of polyQ-expanded androgen receptor (AR) as well as wild type versions of both Htt and AR suggesting a broader involvement of ITSN in neurodegenerative diseases through destabilization of polyQ-containing proteins.


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