# J-domain protein conformational selectivity for tau in disease

> **NIH NIH RF1** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $1,230,000

## Abstract

Tau is a microtubule-associated protein that converts from a healthy shape into beta-sheet rich amyloid
structures which underlie pathology in Alzheimer’s disease and over 20 other related tauopathies. Recent cryo-
EM structures of tau fibrils derived from different tauopathy patient samples reveal structural polymorphisms
that link each tauopathy to distinct amyloid structures. The J-domain protein (JDP) molecular chaperone family
play a central role in regulating tau function to mitigate amyloid assembly in disease. How the diverse family of
JDP molecular chaperones discriminate binding different tau conformations remains poorly understood. My lab
employed a CRISPR knock-out screen for factors that regulate tau aggregation and identified two JDPs,
DnaJC7 and DnaJB6. In recently published worked, we revealed that DnaJC7 has enhanced specificity for
natively folded wild-type tau compared to aggregation-prone mutants or pathogenic seeds. We hypothesize
that the diverse JDP family encodes selectivity for different conformations of substrates. Our data suggests
that novel mechanisms of JDP regulation of tau aggregation could be exploited as both a diagnostic and a
therapeutic intervention. Several important questions remain. How do JDPs that bind to tau discriminate
different tau conformations? Can JDPs modify tau pathology in vivo? In this proposal, we aim to define how a
subset of JDPs recognize different conformations of tau linked to different tau pathologies in cells, in vitro and
in vivo. We will first use biochemical and cellular approaches to understand how JPDs recognize different
conformations of tau. We will also determine structures of tau in complex with DnaJC7 and DnaJB6. Finally,
we will test the activity of DnaJC7 and DnaJB6 on the development of tau pathology in vivo. Our long-term goal
is to develop therapies that can reduce amyloid deposition and slow neurodegeneration. This project is in
alignment with the mission of the NIA to support biological and clinical research on aging.

## Key facts

- **NIH application ID:** 10504392
- **Project number:** 1RF1AG078888-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Lukasz A. Joachimiak
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,230,000
- **Award type:** 1
- **Project period:** 2022-08-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10504392

## Citation

> US National Institutes of Health, RePORTER application 10504392, J-domain protein conformational selectivity for tau in disease (1RF1AG078888-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10504392. Licensed CC0.

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