# Unraveling the role of the molecular co-chaperone DNAJC7 in protein homeostasis and neurodegeneration

> **NIH NIH K08** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $195,570

## Abstract

PROJECT SUMMARY/ABSTRACT
 The aggregation of misfolded proteins is a prominent pathological feature in most age-related
neurodegenerative diseases. This includes Huntington's disease (HD) and various spinocerebellar ataxias,
inherited diseases caused by expanded, aggregation-prone polyglutamine (polyQ) stretches in specific
proteins. Understanding how cells prevent the misfolding of these mutant polyQ proteins holds the potential to
reveal therapeutic strategies not only for polyQ disorders but also for other neurodegenerative conditions.
 I conducted large-scale CRISPR screens for modifiers of polyQ protein aggregation in human cells that
revealed DNAJC7, an Hsp40 co-chaperone, as a top hit. Molecular chaperones are a diverse group of proteins
that assist in proper protein folding, but we lack knowledge about the specific endogenous chaperones most
effective in preventing polyQ protein aggregation, along with their roles in neurons. Importantly, DNAJC7 is
highly expressed in neurons and has connections to other neurodegenerative diseases, leading to the central
hypothesis of this proposal: DNAJC7 is a key neuronal Hsp40 capable of selectively inhibiting aggregation of
amyloidogenic proteins, including mutant polyQ proteins. Aim 1 of this proposal will investigate the impact of
DNAJC7 expression on disease phenotypes in neuronal models of HD, while Aim 2 will delve into DNAJC7’s
mechanism and range of selectivity for different amyloidogenic disease proteins.
 My long-term goal is to establish myself as an academic neuropathologist with a research program
dedicated to studying neuronal protein homeostasis pathways in neurodegeneration. This proposal outlines a
comprehensive 5-year mentored career development plan that will provide me the essential knowledge and
scientific training necessary to successfully transition to this goal. The training plan includes acquiring various
new skills in cutting-edge techniques spanning microscopy, CRISPR functional genomics in iPSC neurons, and
proteomics, as well as enhancing skills in bioinformatics and statistics. Additionally, the training plan covers the
development of professional skills needed to successfully launch and manage a laboratory, including scientific
communication, grant writing, and lab management.
 To achieve these objectives, I have assembled a multidisciplinary mentorship team with complementary
expertise, and includes Dr. Martin Kampmann (mentor), Dr. Eric Huang (co-mentor), and advisory members
Dr. Jason Gestwicki, Dr. Steven Finkbeiner, Dr. Lea Grinberg, and Dr. Arun Wiita. UCSF provides an
exceptional research environment, equipped with cutting-edge technologies and a range of leaders across
multiple disciplines. This proposal will empower me with the necessary skills to establish a thriving and
rigorous independent laboratory, merging with my neuropathology training to become a leader in
neurodegenerative disease research.

## Key facts

- **NIH application ID:** 10984366
- **Project number:** 1K08NS133300-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Biswarathan Ramani
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $195,570
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10984366

## Citation

> US National Institutes of Health, RePORTER application 10984366, Unraveling the role of the molecular co-chaperone DNAJC7 in protein homeostasis and neurodegeneration (1K08NS133300-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10984366. Licensed CC0.

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