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• W2441946812 abstract "Persistent accumulation of misfolded proteins causes endoplasmic reticulum (ER) stress, a prominent feature in many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Here we report the identification of homeodomain interacting protein kinase 2 (HIPK2) as the essential link that promotes ER-stress-induced cell death via the IRE1α-ASK1-JNK pathway. ER stress, induced by tunicamycin or SOD1G93A, activates HIPK2 by phosphorylating highly conserved serine and threonine residues (S359/T360) within the activation loop of the HIPK2 kinase domain. In SOD1G93A mice, loss of HIPK2 delays disease onset, reduces cell death in spinal motor neurons, mitigates glial pathology, and improves survival. Remarkably, HIPK2 activation positively correlates with TDP-43 proteinopathy in NEFH-tTA/tetO-hTDP-43ΔNLS mice, sporadic ALS and C9ORF72 ALS, and blocking HIPK2 kinase activity protects motor neurons from TDP-43 cytotoxicity. These results reveal a previously unrecognized role of HIPK2 activation in ER-stress-mediated neurodegeneration and its potential role as a biomarker and therapeutic target for ALS.Video AbstracteyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiI0YzQ2MTQ4OTNlZmMwMzQ4Zjg1YTllYTg1ZDgwZjg3ZSIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc5MjcyMzQyfQ.Jc2bvI18MfHcnVnpiyrHxQ7skURgQM6QWO_qWJo5qBJTId3L2yOUdT3DPRjaCvh8sxh2DQP8WEKxx6vI94e39ruFgj2X8_ZjqPJYxvaPRNZbIaTWPbiRDRk4gKOuI_fVk3_YoMpFip44pnZ3_IQ46EORRCwu50MWFFHykKSSSrQGxZg718_HhkIPVEfpEU8UL-Gp6nKXuQ6JMd5FQzuuYcp4nVAJHezM0RETmwYowXxT59p8ecwxqYZMZ4fImDV40gmO3zamI8On4d1ktDDLc0pdkb-2bqj_FsR0CLmLKbpV_alpcKy8P3CQvuwQMN3PYYPHEjcf96NLBWSYFEvHMw(mp4, (5.83 MB) Download video" @default.
• W2441946812 created "2016-06-24" @default.
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• W2441946812 date "2016-07-01" @default.
• W2441946812 modified "2023-10-12" @default.
• W2441946812 title "Activation of HIPK2 Promotes ER Stress-Mediated Neurodegeneration in Amyotrophic Lateral Sclerosis" @default.
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• W2441946812 doi "https://doi.org/10.1016/j.neuron.2016.05.021" @default.
• W2441946812 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4938715" @default.
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• W2441946812 hasPublicationYear "2016" @default.
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