Activation of HIPK2 Promotes ER Stress-Mediated Neurodegeneration in Amyotrophic Lateral Sclerosis.
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. VIDEO ABSTRACT.
Department of Pathology, University of California, San Francisco, San Francisco, CA 94158, USA.
Sebum
S
Lee
Department of Pathology, University of California, San Francisco, San Francisco, CA 94158, USA.
Yulei
Y
Shang
Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.
Stephanie A
SA
Redmond
Department of Pathology, University of California, San Francisco, San Francisco, CA 94158, USA.
Anatoly
A
Urisman
Department of Pathology, University of California, San Francisco, San Francisco, CA 94158, USA.
Amy A
AA
Tang
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
Kathy H
KH
Li
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
Alma L
AL
Burlingame
Department of Pathology, University of California, San Francisco, San Francisco, CA 94158, USA.
Ryan A
RA
Pak
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Ana
A
Jovičić
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Aaron D
AD
Gitler
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School & Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Jinhua
J
Wang
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School & Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Nathanael S
NS
Gray
Department of Pathology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
William W
WW
Seeley
Division of Neuromuscular Medicine and Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Teepu
T
Siddique
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Eileen H
EH
Bigio
Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Virginia M-Y
VM
Lee
Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
John Q
JQ
Trojanowski
Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.
Jonah R
JR
Chan
Department of Pathology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA; Pathology Service 113B, VA Medical Center, San Francisco, CA 94121, USA. Electronic address: eric.huang2@ucsf.edu.
Eric J
EJ
Huang
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
D015415:Biomarkers; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D017346:Protein Serine-Threonine Kinases; D013482:Superoxide Dismutase; C578077:Tardbp protein, mouse; C492003:Hipk2 protein, mouse