TY - JOUR AU - Shi, Yingxiao AU - Hung, Shu-Ting AU - Rocha, Gabriel AU - Lin, Shaoyu AU - Linares, Gabriel R. AU - Staats, Kim A. AU - Seah, Carina AU - Wang, Yaoming AU - Chickering, Michael AU - Lai, Jesse AU - Sugawara, Tohru AU - Sagare, Abhay P. AU - Zlokovic, Berislav V. AU - Ichida, Justin K. T1 - Identification and therapeutic rescue of autophagosome and glutamate receptor defects in C9ORF72 and sporadic ALS neurons PY - 2019/08/08/ AB - Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with diverse etiologies. Therefore, the identification of common disease mechanisms and therapeutics targeting these mechanisms could dramatically improve clinical outcomes. To this end, we developed induced motor neuron (iMN) models from C9ORF72 and sporadic ALS patients to identify targets that are effective against these types of cases, which together comprise approximately 90% of patients. We find that iMNs from C9ORF72 and several sporadic ALS patients share 2 common defects — impaired autophagosome formation and the aberrant accumulation of glutamate receptors. Moreover, we show that an anticoagulation-deficient form of activated protein C, 3K3A-APC, rescues these defects in both C9ORF72 and sporadic ALS iMNs. As a result, 3K3A-APC treatment lowers C9ORF72 dipeptide-repeat protein (DPR) levels, restores nuclear TDP-43 localization, and rescues the survival of both C9ORF72 and sporadic ALS iMNs. Importantly, 3K3A-APC also lowers glutamate receptor levels and rescues proteostasis in vivo in C9ORF72 gain- and loss-of-function mouse models. Thus, motor neurons from C9ORF72 and at least a subset of sporadic ALS patients share early defects in autophagosome formation and glutamate receptor homeostasis and a single therapeutic approach may be efficacious against these disease processes. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.127736 VL - 4 IS - 15 UR - https://doi.org/10.1172/jci.insight.127736 PB - The American Society for Clinical Investigation ER -