Differential roles for DNAJ isoforms in HTT-polyQ and FUS aggregation modulation revealed by chaperone screens

Kinneret Rozales,Hodaya Goldman,Lior Kellerman,Shai Berlin,Amal Younis,Reut Shalgi,Anatoly Meller,Ronit Heinrich,Naseeb Saida

doi:10.1038/s41467-022-27982-w

Kinneret Rozales, Hodaya Goldman + Show 7 more

Open Access

https://doi.org/10.1038/s41467-022-27982-w

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Abstract

Protein aggregation is a hallmark of neurodegeneration. Here, we find that Huntington’s disease-related HTT-polyQ aggregation induces a cellular proteotoxic stress response, while ALS-related mutant FUS (mutFUS) aggregation leads to deteriorated proteostasis. Further exploring chaperone function as potential modifiers of pathological aggregation in these contexts, we reveal divergent effects of naturally-occurring chaperone isoforms on different aggregate types. We identify a complex of the full-length (FL) DNAJB14 and DNAJB12, that substantially protects from mutFUS aggregation, in an HSP70-dependent manner. Their naturally-occurring short isoforms, however, do not form a complex, and lose their ability to preclude mutFUS aggregation. In contrast, DNAJB12-short alleviates, while DNAJB12-FL aggravates, HTT-polyQ aggregation. DNAJB14-FL expression increases the mobility of mutFUS aggregates, and restores the deteriorated proteostasis in mutFUS aggregate-containing cells and primary neurons. Our results highlight a maladaptive cellular response to pathological aggregation, and reveal a layer of chaperone network complexity conferred by DNAJ isoforms, in regulation of different aggregate types.

Highlights

IntroductionWe find that Huntington’s disease-related HTT-polyQ aggregation induces a cellular proteotoxic stress response, while amyotrophic lateral sclerosis (ALS)-related mutant FUS (mutFUS) aggregation leads to deteriorated proteostasis
Protein aggregation is a hallmark of neurodegeneration
We show that cells respond differently to different aggregate types; while HTT-polyQ aggregation elicits a proteotoxic stress response, mutant FUS (mutFUS) aggregation leads to deteriorated proteostasis

Summary

Introduction

We find that Huntington’s disease-related HTT-polyQ aggregation induces a cellular proteotoxic stress response, while ALS-related mutant FUS (mutFUS) aggregation leads to deteriorated proteostasis. Our results highlight a maladaptive cellular response to pathological aggregation, and reveal a layer of chaperone network complexity conferred by DNAJ isoforms, in regulation of different aggregate types. We show that cells respond differently to different aggregate types; while HTT-polyQ aggregation elicits a proteotoxic stress response, mutFUS aggregation leads to deteriorated proteostasis. These findings have led us to explore the function of different chaperones, focusing on the HSP70 network, using aggregation modulation screens in human cells, in order to unravel functional diversification in the context of the regulation of different aggregate types

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