Activation of HIPK2 Promotes ER Stress-Mediated Neurodegeneration in Amyotrophic Lateral Sclerosis

Sebum Lee; Yulei Shang; Stephanie A. Redmond; Anatoly Urisman; Amy A. Tang; Kathy H. Li; Alma L. Burlingame; Ryan A. Pak; Ana Jovičić; Aaron D. Gitler; Jinhua Wang; Nathanael S. Gray; William W. Seeley; Teepu Siddique; Eileen H. Bigio; Virginia M.Y. Lee; John Q. Trojanowski; Jonah R. Chan; Eric J. Huang

doi:10.1016/j.neuron.2016.05.021

Activation of HIPK2 Promotes ER Stress-Mediated Neurodegeneration in Amyotrophic Lateral Sclerosis

Sebum Lee, Yulei Shang, Stephanie A. Redmond, Anatoly Urisman, Amy A. Tang, Kathy H. Li, Alma L. Burlingame, Ryan A. Pak, Ana Jovičić, Aaron D. Gitler, Jinhua Wang, Nathanael S. Gray, William W. Seeley, Teepu Siddique, Eileen H. Bigio, Virginia M.Y. Lee, John Q. Trojanowski, Jonah R. Chan, Eric J. Huang^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

66 Scopus citations

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 SOD1^G93A, activates HIPK2 by phosphorylating highly conserved serine and threonine residues (S359/T360) within the activation loop of the HIPK2 kinase domain. In SOD1^G93A 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.

Original language	English (US)
Pages (from-to)	41-55
Number of pages	15
Journal	Neuron
Volume	91
Issue number	1
DOIs	https://doi.org/10.1016/j.neuron.2016.05.021
State	Published - Jul 6 2016

Funding

We thank Linda Kwong, John Robinson, and Theresa Schuck from the Center for Neurodegenerative Disease Research at the University of Pennsylvania for their assistance with NEFH -tTA/ tetO -hTDP-43ΔNLS and human samples; Dr. Kevan Shokat for advice on HIPK2 kinase characterization; and members of the Huang lab for discussions. This work was supported by NIH F31 NS081905-02 (S.A.R.), U54 HG006097-02 (N.S.G.), 8P41GM103481 and 1S10OD016229-01 (A.L.B.), P50 AG023501 and P01 AG019724 (W.W.S.), OD010927 and OD011915 (E.J.H.), AG017586 (V.M.-Y.L.), AG013854 (E.H.B.), NS062796 (J.R.C.), Les Turner ALS Foundation (T.S.), and the Department of Veterans Affairs Merit Review Awards I01-BX001108 and I01-RX002133 (E.J.H.).

ASJC Scopus subject areas

General Neuroscience

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.neuron.2016.05.021

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Lee, S., Shang, Y., Redmond, S. A., Urisman, A., Tang, A. A., Li, K. H., Burlingame, A. L., Pak, R. A., Jovičić, A., Gitler, A. D., Wang, J., Gray, N. S., Seeley, W. W., Siddique, T., Bigio, E. H., Lee, V. M. Y., Trojanowski, J. Q., Chan, J. R., & Huang, E. J. (2016). Activation of HIPK2 Promotes ER Stress-Mediated Neurodegeneration in Amyotrophic Lateral Sclerosis. Neuron, 91(1), 41-55. https://doi.org/10.1016/j.neuron.2016.05.021

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title = "Activation of HIPK2 Promotes ER Stress-Mediated Neurodegeneration in Amyotrophic Lateral Sclerosis",

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.",

author = "Sebum Lee and Yulei Shang and Redmond, {Stephanie A.} and Anatoly Urisman and Tang, {Amy A.} and Li, {Kathy H.} and Burlingame, {Alma L.} and Pak, {Ryan A.} and Ana Jovi{\v c}i{\'c} and Gitler, {Aaron D.} and Jinhua Wang and Gray, {Nathanael S.} and Seeley, {William W.} and Teepu Siddique and Bigio, {Eileen H.} and Lee, {Virginia M.Y.} and Trojanowski, {John Q.} and Chan, {Jonah R.} and Huang, {Eric J.}",

note = "Publisher Copyright: {\textcopyright} 2016",

year = "2016",

month = jul,

day = "6",

doi = "10.1016/j.neuron.2016.05.021",

language = "English (US)",

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Lee, S, Shang, Y, Redmond, SA, Urisman, A, Tang, AA, Li, KH, Burlingame, AL, Pak, RA, Jovičić, A, Gitler, AD, Wang, J, Gray, NS, Seeley, WW, Siddique, T, Bigio, EH, Lee, VMY, Trojanowski, JQ, Chan, JR & Huang, EJ 2016, 'Activation of HIPK2 Promotes ER Stress-Mediated Neurodegeneration in Amyotrophic Lateral Sclerosis', Neuron, vol. 91, no. 1, pp. 41-55. https://doi.org/10.1016/j.neuron.2016.05.021

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T1 - Activation of HIPK2 Promotes ER Stress-Mediated Neurodegeneration in Amyotrophic Lateral Sclerosis

AU - Lee, Sebum

AU - Shang, Yulei

AU - Redmond, Stephanie A.

AU - Urisman, Anatoly

AU - Tang, Amy A.

AU - Li, Kathy H.

AU - Burlingame, Alma L.

AU - Pak, Ryan A.

AU - Jovičić, Ana

AU - Gitler, Aaron D.

AU - Wang, Jinhua

AU - Gray, Nathanael S.

AU - Seeley, William W.

AU - Siddique, Teepu

AU - Bigio, Eileen H.

AU - Lee, Virginia M.Y.

AU - Trojanowski, John Q.

AU - Chan, Jonah R.

AU - Huang, Eric J.

PY - 2016/7/6

Y1 - 2016/7/6

N2 - 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.

AB - 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.

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Activation of HIPK2 Promotes ER Stress-Mediated Neurodegeneration in Amyotrophic Lateral Sclerosis

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