CEP-1347 reduces mutant huntingtin-associated neurotoxicity and restores BDNF levels in R6/2 mice.
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.
Apostol
Barbara L
BL
Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697, USA.
Simmons
Danielle A
DA
Zuccato
Chiara
C
Illes
Katalin
K
Pallos
Judit
J
Casale
Malcolm
M
Conforti
Paola
P
Ramos
Catarina
C
Roarke
Margaret
M
Kathuria
Satish
S
Cattaneo
Elena
E
Marsh
J Lawrence
JL
Thompson
Leslie Michels
LM
D000818:Animals; D030801:Animals, Genetically Modified; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002227:Carbazoles / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D002460:Cell Line; D004195:Disease Models, Animal; D004331:Drosophila melanogaster; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism; D026121:Indole Alkaloids / Q000737:chemistry / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity*; D010641:Phenotype; D051381:Rats
D019208:Brain-Derived Neurotrophic Factor; C469298:CEP-11004; D002227:Carbazoles; D004791:Enzyme Inhibitors; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D026121:Indole Alkaloids; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; C106592:3,9-bis((ethylthio)methyl)-K-252a; C049985:staurosporine aglycone; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases