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

Neuron. 2016 Jul 6;91(1):41-55. doi: 10.1016/j.neuron.2016.05.021. Epub 2016 Jun 16.

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. VIDEO ABSTRACT.

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Biomarkers / analysis
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Death
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism*
  • Mice, Transgenic
  • Motor Neurons / metabolism*
  • Neuroglia / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Spinal Cord / metabolism
  • Superoxide Dismutase / metabolism

Substances

  • Biomarkers
  • Carrier Proteins
  • DNA-Binding Proteins
  • TDP-43 protein, mouse
  • Superoxide Dismutase
  • Hipk2 protein, mouse
  • Protein Serine-Threonine Kinases