Mutant huntingtin alters MAPK signaling pathways in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity.
Huntington's disease (HD) is a devastating neurodegenerative disorder caused by an expanded polyglutamine (polyQ) tract within the huntingtin protein (Htt). Identifying the pathways that are altered in response to the mutant protein is crucial for understanding the cellular processes impacted by the disease as well as for the rational development of effective pharmacological interventions. Here, expression profiling of a cellular HD model identifies genes that implicate altered mitogen-activated protein kinase (MAPK) signaling. Targeted biochemical studies and pharmacological modulation of these MAPK pathways suggest that mutant Htt affects signaling at upstream points such that both ERK and JNK are activated. Modulation of the ERK pathway suggests that this pathway is associated with cell survival, whereas inhibition of JNK was found to effectively suppress pathogenesis. These studies suggest that pharmacological intervention in MAPK pathways, particularly at the level of ERK activation, may be an appropriate approach to HD therapy.
Apostol
Barbara L
BL
Department of Psychiatry and Human Behavior, University of California, Irvine, 92697, USA.
Illes
Katalin
K
Pallos
Judit
J
Bodai
Laszlo
L
Wu
Jun
J
Strand
Andrew
A
Schweitzer
Erik S
ES
Olson
James M
JM
Kazantsev
Aleksey
A
Marsh
J Lawrence
JL
Thompson
Leslie Michels
LM
D000818:Animals; D015152:Blotting, Northern; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D017931:DNA Primers; D004789:Enzyme Activation / Q000235:genetics; D020869:Gene Expression Profiling; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics*; D046228:Microarray Analysis; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D051381:Rats; D015398:Signal Transduction / Q000235:genetics*
D017931:DNA Primers; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D020928:Mitogen-Activated Protein Kinases