# Anisosmotic Modulation of Mutant Huntingtin Aggregation vis-a-vis HSP70 InductionImplications for Aging, Hypo-Hydration, and Neurodegeneration

## TL;DR

This study shows how cell hydration affects protein aggregation and stress response, with implications for aging and neurodegenerative diseases.

## Contribution

The study reveals how osmotic modulation influences mutant Huntingtin aggregation and HSP70 induction in Huntington disease models.

## Key findings

- Sodium chloride and alkali-metal salts promote mutant Huntingtin aggregation and reduce HSP70 induction.
- Hypo-osmotic conditions reduce protein aggregation and increase HSP70 levels.
- PEGs also promote mutant Huntingtin aggregation, similar to salt treatments.

## Abstract

Suboptimal cell hydration is a significant risk factor
for age-related
deterioration and disease vulnerability. Herein, we use a Huntington
disease cell model to evaluate osmolarity-dependent modulation of
(1) aggregation of polyQ-expanded mutant Huntingtin-EGFP reporter
protein as a readout for structurally dynamic disease proteins versus
(2) induction of HSP70 chaperone to report on stress-induced lability
of folded proteins. Cell impermeant alkali-metal salts and polyethylene
glycols were added to cell media to osmotically dehydrate cells for
crowding, whereas water was added to swell cells for macromolecular
dispersion. Cell image and biochemical analyses show that addition
of sodium chloride and other alkali-metal salts to cell media promoted
aggregation of mHTTExon1-EGFP protein into forming “inclusion
bodies” (IBs) in live cells, while concurrently dampened the
induction of HSP70 by heat shock. Conversely, a hypo-osmotic medium
tempered the compaction of mHTTExon1-EGFP into forming
IBs while increasing the induction of HSP70. Cell impermeable PEGs
likewise promoted mHTTExon1-EGFP aggregation. These observations
underscore the importance of an iso-osmotic cell environment for balanced
structure and function of disordered versus folded proteome, that
deviations from this ideal carry dire consequences on protein homeostasis
conducive to disease protein aggregation and stress vulnerability.