Mutant huntingtin alters cell fate in response to microtubule depolymerization via the GEF-H1-RhoA-ERK pathway

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