Editors' ChoiceNeurodegeneration

JNK Slowdown

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Science Signaling  07 Jul 2009:
Vol. 2, Issue 78, pp. ec230
DOI: 10.1126/scisignal.278ec230

The genetic basis of Huntington’s disease is the expansion of a CAG trinucleotide in the huntingtin (HTT) gene; these CAG repeats result in the insertion of stretches of polyglutamine (polyQ) residues in the Htt protein. Although the mutant protein (polyQ-Htt) is produced ubiquitously, it is selectively toxic to neurons, a property that has been partially attributed to its ability to inhibit fast axonal transport (FAT). Morfini et al. show that polyQ-Htt does not inhibit FAT by interacting directly with motor proteins, but rather by promoting phosphorylation of kinesin-1. Addition of polyQ-Htt to isolated squid axoplasm stimulated JNK (c-Jun N-terminal kinase) activity. The brains of HttQ109 knock-in mice (which express a gene encoding Htt with 109 additional Gln residues) contained more phosphorylated and activated JNK2 and JNK3 compared with wild-type mice. Moreover, addition of purified JNK3, but not JNK1 or JNK2, mimicked the inhibition of FAT by polyQ-Htt. In mammals, JNK1 and JNK2 are ubiquitously expressed, whereas JNK3 is restricted to certain tissues, including the brain. JNK3 phosphorylated kinesin-1 at Ser176, which is located in a region thought to mediate the binding of kinesin-1 to microtubules. Accordingly, kinesin-1 binding to microtubules was lower in cells expressing polyQ-Htt compared with those expressing wild-type Htt. In hippocampal cells, translocation of a kinesin-1 construct tagged with green fluorescent protein was decreased by mutation of the Ser176 to glutamate (a mutation that mimics phosphorylation) but not to alanine (which creates a nonphosphorylatable mutant). Thus, the authors propose that the activation of JNK3 by mutant Htt and the subsequent inhibition of FAT may be key events underlying the neurodegeneration seen in Huntington’s disease.

G. A. Morfini, Y.-M. You, S. L. Pollema, A. Kaminska, K. Liu, K. Yoshioka, B. Björkblom, E. T. Coffey, C. Bagnato, D. Han, C.-F. Huang, G. Banker, G. Pigino, S. T. Brady, Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin. Nat. Neurosci. 12, 864–871 (2009). [PubMed]

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