# Mechanisms of ER Stress and Neurodegeneration in Amyotrophic Lateral Sclerosis

> **NIH VA I01** · VETERANS AFFAIRS MED CTR SAN FRANCISCO · 2023 · —

## Abstract

Neurodegenerative diseases are characterized by accumulation of misfolded proteins in disease-specific neural
circuits, which disrupts normal neuronal functions, including axonal transport, mitochondrial bioenergetics, gene
expression, and synaptic connectivity. In addition, there is compelling evidence that neuroinflammation can also
initiate and/or facilitate disease progression. These results support an interconnected mechanism, in which
protein misfolding and neuroinflammation synergistically promote disease progression in a feed-forward manner.
Among the major neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) affects upper and lower motor
neurons and is often associated with aggressive clinical courses. Although the majority of ALS cases are
sporadic, ~10% are caused by mutations that affect RNA metabolism, intracellular vesicular trafficking, and
protein homeostasis via the ubiquitin-proteasome pathways (proteostasis). Characterizations of these cellular
functions provide critical windows to understand disease mechanism and to intervene its onset and progression.
During the past funding period, we showed that misfolded proteins activate endoplasmic reticulum (ER) stress
and its downstream signaling pathways, including stress-activated kinase, homeodomain interacting protein
kinase 2 (HIPK2), to promote neuronal cell death. We developed highly sensitive biochemical, morphological
and functional assays to show that ER stress activates HIPK2 and that HIPK2 activation can be detected in the
spinal motor neurons of pre-symptomatic SOD1G93A and NEFH-tTA/tetO-hTDP-43DNLS mouse ALS models,
suggesting that HIPK2 activation directly contributes to neurodegeneration. In support of this idea, loss of HIPK2
or blocking HIPK2 kinase activity significantly protects motor neurons from cell death induced by SOD1G93A or
TDP-43. To broaden our understanding of HIPK2 in neurodegeneration, we further showed that HIPK2 can
regulate neuronal survival and cell death via transcriptional regulation of gene expression and by regulating
Parkin protein levels via proteasome-mediated pathway. In addition, we performed proteomic screens to
characterize HIPK2 interactomes and identified HSPA9 (also known as Mortalin) as a HIPK2 interacting partner.
Together, these results support the hypothesis that HIPK2 and its interactomes regulate a delicate balance of
neuronal survival and cell death via both cell autonomous and glia-mediated mechanisms. To test this, we
propose to (1) characterize the role of HSPA9 in neuronal cell death during development and in
neurodegeneration, (2) delineate the mechanism of HIPK2 in neuroinflammation in ALS, and (3) perform single
cell transcriptomics to elucidate the role of ER stress and neuroinflammation in SALS and C9-ALS. Collectively,
results from this proposal will provide a more complete understanding of the cellular and molecular mechanisms
of HIPK2 in stress-induced neurodegeneration in ALS.

## Key facts

- **NIH application ID:** 10620231
- **Project number:** 5I01BX001108-11
- **Recipient organization:** VETERANS AFFAIRS MED CTR SAN FRANCISCO
- **Principal Investigator:** Eric J Huang
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2011-07-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10620231

## Citation

> US National Institutes of Health, RePORTER application 10620231, Mechanisms of ER Stress and Neurodegeneration in Amyotrophic Lateral Sclerosis (5I01BX001108-11). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10620231. Licensed CC0.

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