# Defining the mechanisms by which mutations in DNAJC7 increase susceptibility to ALS/FTD

> **NIH NIH F31** · NORTHWESTERN UNIVERSITY · 2023 · $47,694

## Abstract

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 spinal motor neurons (MNS) 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, which is
based on our preliminary finding that DNAJC7 interacts with the ALS-causal RNA metabolism protein MATR3,
we will determine if pathogenic mutations in DNAJC7 impede MATR3 folding. Next, we will investigate the
functional consequences of disruptions in DNAJC7-substrate interface by measuring how DNAJC7 mutations
affect MATR3-associated RNA processing in patient MNs. In Aim 2, which is based on our preliminary finding
that DNAJC7 impedes the HSF1 response, we will define the mechanistic role DNAJC7 plays in the HSF1-
mediated stress response in patient derived mutant and isogenic control MNs. We will directly measure DNAJC7-
dependent loss of HSF1 transcriptional activity upon stress, determine if DNAJC7 is involved in the dissociation
of the inhibitory HSP70-HSF1 complex, and methodically characterize disruptions in protein solubility caused by
pathogenic DNAJC7 using MS-based proteomics approaches. Taken together, our proposed aims will shed light
upon the cellular mechanisms that are compromised by DNAJC7 haploinsufficiency. 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...

## Key facts

- **NIH application ID:** 10679697
- **Project number:** 1F31NS132580-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Andrew Fleming
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $47,694
- **Award type:** 1
- **Project period:** 2023-09-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10679697

## Citation

> US National Institutes of Health, RePORTER application 10679697, Defining the mechanisms by which mutations in DNAJC7 increase susceptibility to ALS/FTD (1F31NS132580-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10679697. Licensed CC0.

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