Universität zu Köln

Koyuncu, Seda ORCID: 0000-0001-7937-3974, Dominguez-Canterla, Yaiza, Alis, Rafael, Salarzai, Nassima, Petrovic, Dunja, Flames, Nuria and Vilchez, David ORCID: 0000-0002-0801-0743 (2025). The aging factor EPS8 induces disease-related protein aggregation through RAC signaling hyperactivation. Nature Aging, 5 (9). pp. 1750-1770. Nature Publ. Group. ISSN 2662-8465

PDF s43587-025-00943-w.pdf Bereitstellung unter der CC-Lizenz: Creative Commons Attribution. Download (7MB)

Abstract

Aging is a major risk factor for neurodegenerative diseases associated with protein aggregation, including Huntington’s disease and amyotrophic lateral sclerosis (ALS). Although these diseases involve different aggregation-prone proteins, their common late onset suggests a link to converging changes resulting from aging. In this study, we found that age-associated hyperacti- vation of EPS8/RAC signaling in Caenorhabditis elegans promotes the pathological aggregation of Huntington’s disease-related polyglutamine repeats and ALS-associated mutant FUS and TDP-43 variants. Conversely, knockdown of eps-8 or RAC orthologs prevents protein aggregation and subsequent deficits in neuronal function during aging. Similarly, inhibiting EPS8 signaling reduces protein aggregation and neurodegeneration in human cell models. We further identify the deubiquitinating enzyme USP4 as a regulator of EPS8 ubiquitination and degradation in both worms and human cells. Notably, reducing USP-4 upregulation during aging prevents EPS-8 accumulation, extends longevity and attenuates disease-related changes. Our findings suggest that targeting EPS8 and its regulatory mechanisms could provide therapeutic strategies for age-related diseases.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Koyuncu, Seda UNSPECIFIED https://orcid.org/0000-0001-7937-3974 UNSPECIFIED Dominguez-Canterla, Yaiza UNSPECIFIED UNSPECIFIED UNSPECIFIED Alis, Rafael UNSPECIFIED UNSPECIFIED UNSPECIFIED Salarzai, Nassima UNSPECIFIED UNSPECIFIED UNSPECIFIED Petrovic, Dunja UNSPECIFIED UNSPECIFIED UNSPECIFIED Flames, Nuria UNSPECIFIED UNSPECIFIED UNSPECIFIED Vilchez, David UNSPECIFIED https://orcid.org/0000-0002-0801-0743 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-811829
Identification Number:	10.1038/s43587-025-00943-w
Journal or Publication Title:	Nature Aging
Volume:	5
Number:	9
Page Range:	pp. 1750-1770
Number of Pages:	21
Date:	3 September 2025
Publisher:	Nature Publ. Group
ISSN:	2662-8465
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences Faculty of Medicine
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics Zentrum für Molekulare Medizin
Subjects:	Life sciences Medical sciences Medicine
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/81182