# Mechanisms of HIPK2 in neurodegeneration

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $346,719

## Abstract

PROJECT SUMMARY
Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is an adult-onset neurodegenerative disease that
affects upper and lower motor neurons. The key clinical features in ALS patients include muscle wasting, and
progressive loss of spinal motor neurons and upper motor neurons and their axons in the lateral columns of the
spinal cord. The past 10 years have witnessed a tremendous expansion in the molecular mechanisms of this
devastating disease thanks to the discoveries of genetic mutations that are causally linked to both familial ALS
(FALS) and sporadic ALS (SALS). Characterizations of these “ALS disease genes” suggest that dysfunctions
in protein homeostasis via the ubiquitin-proteasome pathways (proteostasis) might contribute to the
pathogenesis and disease progression in ALS. Consistent with the genetic data, a key pathological feature in
FALS and SALS is accumulation of misfolded proteins in motor neurons, which disrupts normal neuronal
functions, including axonal transport, mitochondrial bioenergetics, gene expression, and synaptic connectivity.
Persistent accumulation of misfolded proteins eventually triggers endoplasmic reticulum (ER) stress-induced
cell death, which leads to neurodegeneration through mechanisms that are poorly understood. This proposal
focuses on the neuronal cell death mechanism downstream of the IRE1α pathway of ER stress. We show that
ER stress, induced pharmacologically or by mutant SOD1 proteins, activates a highly conserved kinase HIPK2
(homeodomain interacting protein kinase 2) to promote neuronal cell death. Biochemical evidence shows that
HIPK2 acts downstream of IRE1α-ASK1 and upstream of JNK to promote ER stress-mediated cell death. In
addition, proteomics, phospho-peptide mapping and mutagenesis further show that ER stress activates HIPK2
by promoting phosphorylation on specific Serine and Threonine residues within the kinase domain. Using
phospho-HIPK2-specific antibodies, we show that HIPK2 activation in the spinal cord precedes symptom onset
in SOD1G93A mice. Importantly, loss of HIPK2 in SOD1G93A;Hipk2-/- mice mitigates neurodegeneration, delays
disease onset and prolongs survival. Finally, we have extended our findings of HIPK2 in ER stress to human
disease using a large number of spinal cord tissues from FALS and SALS patients. Together, these results
support the hypothesis that HIPK2 is an essential target in the downstream of IRE1α pathway that promotes
ER stress-induced neuronal cell death in ALS. We propose three multidisciplinary Aims to investigate the
robust, yet previously unappreciated role of HIPK2 in ER stress-induced cell death mechanism in ALS. Results
from these studies will not only address a major challenge in understanding disease mechanism in ALS, they
will also provide new directions to develop potential therapeutic targets to mitigate neuronal cell death in ALS.

## Key facts

- **NIH application ID:** 9975934
- **Project number:** 5R01NS098516-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Eric J Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $346,719
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975934

## Citation

> US National Institutes of Health, RePORTER application 9975934, Mechanisms of HIPK2 in neurodegeneration (5R01NS098516-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9975934. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*