# A Holistic Approach to Understanding Small Heat Shock Protein Mechanism

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $336,456

## Abstract

PROJECT SUMMARY/ABSTRACT
We propose to define the molecular mechanisms of two underappreciated dementia syndromes known as
Familial Danish Dementia and Familial British Dementia. Both syndromes have highly similar pathologies to
Alzheimer’s Disease (AD), with onset of dementia as early as 40 years of age. While a majority of AD is age-
related, sporadic, and can be caused by a myriad of events or dysfunctions, the genetic cause of the Familial
dementia syndromes is identified as mutations in the gene that encodes for an integral membrane protein,
BRI-2. Normally, maturation of BRI-2 involves proteolytic processing that generates a 23-residue peptide.
However, the BRI2-derived peptides generated from the mutant BRI-2 proteins are each extended by 11
residues. The extensions differ between Danish and British dementia because the causative mutations differ.
Notably, the earliest manifestation of Danish dementia syndrome is the appearance of cataracts at ages as
early as 20 years, while no ocular symptoms are reported for British dementia patients. The Danish dementia
peptide has been shown to bind to the major protein chaperone responsible for maintaining lens transparency,
-crystallin (HSPB4/HSPB5) and to interfere with its ability to function as a chaperone against model client
proteins, while the British dementia peptide was a much less effective inhibitor of lens chaperone function.
Both Danish and British patients suffer from early-onset dementia, suggesting a shared ability to accelerate
aggregation processes that lead to amyloid plaques and neurofibrillary tangles. This dichotomy provides a
powerful strategy for defining the key features responsible for 1) protein aggregation that leads to
development of cataracts in Danish patients and 2) accelerated aggregation and plaque formation in both
Danish and British patients. We propose to employ protein reagents and experimental approaches developed
in the ongoing parent grant to investigate how familial dementia peptides interfere with 1) HSPB4/HSPB5
chaperone function towards a lens-specific protein client (D-crystallin) and 2) HSPB1/HSPB5 chaperone
function towards the amyloidogenic protein, Tau. Our approaches include: aggregation assays using bona
fide protein clients under physiologically relevant conditions, quantitative determination of intermolecular
interactions, mapping of interactions at the residue-level by NMR and UV-crosslinking/mass spectrometry,
among others. The chaperones under investigation are constitutively expressed in lens, neurons, and brain
and likely serve to stave off harmful protein aggregation for most of an individual’s lifetime. Understanding the
molecular mechanism of these familial dementias and how chaperone function is disrupted provides a novel
path to understand a broad array of AD/ADRDs and potentially to shore up intrinsic systems such as the small
heat shock protein chaperones to delay and inhibit protein aggregation and amyloid formation throughout an
in...

## Key facts

- **NIH application ID:** 10936874
- **Project number:** 3R01EY017370-16S1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Rachel E Klevit
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $336,456
- **Award type:** 3
- **Project period:** 2007-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10936874

## Citation

> US National Institutes of Health, RePORTER application 10936874, A Holistic Approach to Understanding Small Heat Shock Protein Mechanism (3R01EY017370-16S1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10936874. Licensed CC0.

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