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Protein misfolding is a prominent feature in amyotrophic lateral sclerosis (ALS)
TDP-43 Ubiquitin
FUS/TLS Ubiquitin
p
ATF6IRE1a
RNase
Misfoldedproteins
PERK Kinase
Protein misfolding activates endoplasmic reticulum (ER) stress
p
ATF6IRE1a
RNase
Pre-Xbp1 RNA Mature Xbp1 mRNA
Misfoldedproteins
PERK Kinase
Protein misfolding activates endoplasmic reticulum (ER) stress
miRNAProtein quality control
p
ATF6IRE1a
RNase
Pre-Xbp1 RNA Mature Xbp1 mRNA
Misfoldedproteins
PERK Kinase
Protein misfolding activates endoplasmic reticulum (ER) stress
?ASK1 p
NeuronalDeathpJNK
Homeodomain interacting protein kinase 2 (HIPK2)
Brn3a, Nkx, Pax6Smad1/2/3, c-Skic-myb, NLK, p53p300, Runx1 (AML1)
Protein-proteininteraction domainS/T/Y kinase domain
SRS 1189 a.a.HIPK2NLS
CtBP/-catenin(Corepressor domain)
(SUMO)K25
(Ubi)K1182PEST
Cellular response to DNA damage
Vascular development
Neuronal survival & cell death
Wiggins et al., J Cell Biol 2004Zhang et al., Nature Neurosci 2007Wei et al., PNAS 2007Chalazonitis et al., J Neurosci 2012
p
ATF6IRE1a
RNase
Pre-Xbp1 RNA Mature Xbp1 mRNA
Misfoldedproteins
PERK Kinase
Protein misfolding activates endoplasmic reticulum (ER) stress
NeuronalDeath
HIPK2 knockoutfibroblasts & neurons
Tunicamycin
Biochemical approaches reveal epitope-specific HIPK2 activation during ER stress
1 192 520 583 897 1189
Kinase domain
S359 T360 Y361
P P
ASK1 PP
1
2
2
HIPK2Interactiondomain
ER Stress & IRE1α activation
1 192 520 583 897 1189
Kinase domain
S359 T360 Y361
P P
Activation ofHIPK2 kinase
ASK1 PP
1
2
2
3HIPK2Interaction
domain
ER Stress & IRE1α activation
1 192 520 583 897 1189
Kinase domain
S359 T360 Y361
583 798
P P
Activation ofHIPK2 kinase
JNK PP
ASK1 PP
1
2
2
34
HIPK2Interactiondomain
ER Stress & IRE1α activation
Loss of HIPK2 delays disease onset and prolongs survival in SOD1G93A mice
Distinct role of HIPK2 & ER stress pathway in different ALS models
ALS-FUS-R521CDendrite/Synaptic
defectsBDNF/TrkB SignalingTranscription & RNA
splicingDNA damage repairNeuroinflammation
ALS-SOD1G93A
ER Stress/UPRCell Death
Oligodendroglia Defects
Axonal TransportMitochondrial
DefectsNeuroinflammation
ALS-hTDPDNLS
ER Stress/UPRTranscription &
RNA SplicingNucleosome
AssemblyCell Death
Distinct role of HIPK2 & ER stress pathway in different ALS models
ALS-FUS-R521CDendrite/Synaptic
defectsBDNF/TrkB SignalingTranscription & RNA
splicingDNA damage repairNeuroinflammation
ALS-SOD1G93A
ER Stress/UPRCell Death
Oligodendroglia Defects
Axonal TransportMitochondrial
DefectsNeuroinflammation
ALS-hTDPDNLS
ER Stress/UPRTranscription &
RNA SplicingNucleosome
AssemblyCell Death
✗✔ ✔
Sporadic ALS (TDP proteinopathy)
ER stress/UPRHIPK2 and JNK activation
Neurodegeneration
Misfolded proteins in FALS and SALS activate HIPK2 in ER stress pathway
ALS-C9orf72
ER Stress/UPRDipeptide repeat
toxicityRNA toxicity
Nuclear pore defectLOF in C9orf72
Microglial activation
ALS-FUS-R521CDendrite/Synaptic
defectsBDNF/TrkB SignalingTranscription & RNA
splicingDNA damage repairNeuroinflammation
ALS-SOD1G93A
ER Stress/UPRCell Death
Oligodendroglia Defects
Axonal TransportMitochondrial
DefectsNeuroinflammation
ALS-hTDPDNLS
ER Stress/UPRTranscription &
RNA SplicingNucleosome
AssemblyCell Death
✗✔ ✔
HIPK2 activation positively correlates with TDP-43 proteinopathy in C9-ALS and SALS
p
p
ATF6IRE1a
RNase
Pre-Xbp1 RNA Mature Xbp1 mRNA
Misfoldedproteins
PERK Kinase
HIPK2JNK
ASK1 p
pp
NeuronalDeath
GlialToxicity
Protein misfolding activates endoplasmic reticulum (ER) stress
TunicamycinTg-SOD1G93A
Tg-hTDP-43ΔNLSSALS/C9-ALS
** Special thanks to Claire Huang for video/audio production & editing
Modeling of HIPK2 kinase domain reveals epitope activated during ER stress
ER Stress & IRE1α activation
ASK1 PP
1
