# Defining the Mechanisms by Which Mutations in DNAJC7 Increase Susceptibility to ALS/FTD

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2024 · $189,915

## Abstract

The accumulation of insoluble and misfolded proteins is commonly associated with degeneration of neurons in
amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. Heat shock proteins (HSPs)
play a central role in the regulation of protein homeostasis by facilitating effective folding, trafficking, and
degradation of both nascent and aged polypeptides. While it has become increasingly clear that perturbations in
in the proteostasis network play a significant role in ALS/FTD, limited emphasis has been placed on investigating
the direct causal relationship between the functionality of HSPs and disease pathogenesis. Heterozygous, loss-
of-function mutations in the DNAJC7 gene, which encodes for the HSP40 protein DNAJC7 have recently been
identified as a cause for rare forms of ALS. The DNAJC7 protein acts as a co-chaperone for HSP70 chaperones,
thereby facilitating HSP70-polypeptide interactions and appropriate polypeptide folding. However, little is known
about the specific function of DNAJC7 in the central nervous system and motor neurons specifically, the cell type
that predominantly degenerates in ALS patients. Our primary hypothesis is that DNAJC7 haploinsufficiency leads
to the accumulation of misfolded HSP70 client proteins resulting in the disruption of biological processes critical
to the function and survival of vulnerable MNs. Here, we will use mutant DNAJC7 cellular models, patient induced
pluripotent stem cell (iPSC)-derived cortical and spinal motor neurons and CRISPR/Cas9 gene-editing, in
combination with mass spectrometry (MS)-based quantitative proteomics and RNA-Sequencing to elucidate how
ALS/FTD-associated mutations in DNAJC7 contribute towards neuronal dysfunction and degeneration. In Aim 1
we will determine the endogenous interactome of DNAJC7 in mutant and isogenic control human neurons to
better understand the functional role that it plays in postmitotic cells. In Aim 2 we will methodically characterize
disruptions in protein folding caused by pathogenic DNAJC7 using two independent MS-based proteomics
approaches. These experiments will provide an unbiased proteome-wide interrogation of fundamental aspects
of proteostasis in ALS-DNAJC7 mutant and isogenic control neurons. In Aim 3, which is based on our preliminary
finding that DNAJC7 interacts with the ALS-casual RNA-metabolism proteins FUS and MATR3, we will
investigate how DNAJC7 mutations affect RNA processing in patient neurons. Taken together, our proposed
aims will shed light upon the cellular mechanisms that are compromised by DNAJC7 haploinsufficiency in distinct
human cortical and spinal neurons. Our findings will impact the field by contributing towards the understanding
of HSP-dependent proteostasis mechanisms in human neurons as well as to how rare ALS genetic mutations
lead to neuron dysfunction and loss. Identifying novel proteins that are susceptible to misfolding in human
neurons might highlight cellular pathways critical for ALS/FTD p...

## Key facts

- **NIH application ID:** 10765698
- **Project number:** 5R21NS131713-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Evangelos Kiskinis
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $189,915
- **Award type:** 5
- **Project period:** 2023-01-18 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765698

## Citation

> US National Institutes of Health, RePORTER application 10765698, Defining the Mechanisms by Which Mutations in DNAJC7 Increase Susceptibility to ALS/FTD (5R21NS131713-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10765698. Licensed CC0.

---

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