Huntington's disease (HD) is a devastating neurodegenerative disorder caused by an
expanded polyglutamine repeat within the protein Huntingtin (Htt). We previously reported
that mutant Htt expression activates the ERK1/2 and JNK pathways [Apostol, B.L., Illes,
K., Pallos, J., Bodai, L., Wu, J., Strand, A., Schweitzer, E.S., Olson, J.M., Kazantsev,
A., Marsh, J.L., Thompson, L.M., 2006. Mutant huntingtin alters MAPK signaling pathways
in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity.
Hum. Mol. Genet. 15, 273-285]. Chemical and genetic modulation of these pathways promotes
cell survival and death, respectively. Here we test the ability of two closely related
compounds, CEP-11004 and CEP-1347, which inhibit Mixed Lineage Kinases (MLKs) and
are neuroprotective, to suppress mutant Htt-mediated pathogenesis in multiple model
systems. CEP-11004/CEP-1347 treatment significantly decreased toxicity in mutant Htt-expressing
cells that evoke a strong JNK response. However, suppression of cellular dysfunction
in cell lines that exhibit only mild Htt-associated toxicity and little JNK activation
was associated with activation of ERK1/2. These compounds also reduced neurotoxicity
in immortalized striatal neurons from mutant knock-in mice and Drosophila expressing
a mutant Htt fragment. Finally, CEP-1347 improved motor performance in R6/2 mice and
restored expression of BDNF, a critical neurotrophic factor that is reduced in HD.
These studies suggest a novel therapeutic approach for a currently untreatable neurodegenerative
disease, HD, via CEP-1347 up-regulation of BDNF.