Mutant Huntingtin Alters Cell Fate in Response to Microtubule Depolymerization via the GEF-H1-RhoA-ERK Pathway *

摘要: Cellular responses to drug treatment show tremendous variations. Elucidating mechanisms underlying these variations is critical for predicting therapeutic and developing personalized therapeutics. Using a small molecule screening approach, we discovered how disease causing allele leads opposing cell fates upon pharmacological perturbation. Diverse microtubule-depolymerizing agents protected mutant huntingtin-expressing cells from death, while being toxic lacking huntingtin or those expressing wild-type huntingtin. Additional neuronal lines primary neurons Huntington mice also showed altered survival microtubule depolymerization. Transcription profiling revealed that depolymerization induced the autocrine growth factor connective tissue activated ERK signaling. The genotype-selective rescue was dependent increased RhoA protein levels in cells, because inhibition of RhoA, its downstream effector, Rho-associated kinase (ROCK), microtubule-associated activator, guanine nucleotide exchange factor-H1 (GEF-H1), all attenuated rescue. Conversely, overexpression conferred resistance microtubule-depolymerizer toxicity. This study elucidates novel pathway linking stability provides insight into genetic context can dramatically alter cellular interventions.