Universität zu Köln

Alirzayeva, Hafiza, Loureiro, Rute ORCID: 0000-0002-2023-2429, Koyuncu, Seda ORCID: 0000-0001-7937-3974, Hommen, Franziska ORCID: 0000-0002-1612-6973, Nabawi, Yara, Zhang, William Hongyu ORCID: 0000-0002-2191-3576, Dao, Thien T.P. ORCID: 0000-0002-5408-7442, Wehrmann, Markus ORCID: 0000-0001-7511-7471, Lee, Hyun Ju and Vilchez, David ORCID: 0000-0002-0801-0743 (2024). ALS-FUS mutations cause abnormal PARylation and histone H1.2 interaction, leading to pathological changes. Cell Reports, 43 (8). pp. 1-25. Elsevier. ISSN 2211-1247

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Abstract

[Artikel-Nr.: 114626] The majority of severe early-onset and juvenile cases of amyotrophic lateral sclerosis (ALS) are caused by mutations in the FUS gene, resulting in rapid disease progression. Mutant FUS accumulates within stress granules (SGs), thereby affecting the dynamics of these ribonucleoprotein complexes. Here, we define the interactome of the severe mutant FUSP525L variant in human induced pluripotent stem cell (iPSC)-derived motor neurons. We find increased interaction of FUSP525L with the PARP1 enzyme, promoting poly-ADP-ribosylation (PARylation) and binding of FUS to histone H1.2. Inhibiting PARylation or reducing H1.2 levels alleviates mutant FUS aggregation, SG alterations, and apoptosis in human motor neurons. Conversely, elevated H1.2 levels exacerbate FUS-ALS phenotypes, driven by the internally disordered terminal domains of H1.2. In C. elegans models, knockdown of H1.2 and PARP1 orthologs also decreases FUSP525L aggregation and neurodegeneration, whereas H1.2 overexpression worsens ALS-related changes. Our findings indicate a link between PARylation, H1.2, and FUS with potential therapeutic implications.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Alirzayeva, Hafiza UNSPECIFIED UNSPECIFIED UNSPECIFIED Loureiro, Rute UNSPECIFIED https://orcid.org/0000-0002-2023-2429 UNSPECIFIED Koyuncu, Seda UNSPECIFIED https://orcid.org/0000-0001-7937-3974 UNSPECIFIED Hommen, Franziska UNSPECIFIED https://orcid.org/0000-0002-1612-6973 UNSPECIFIED Nabawi, Yara UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhang, William Hongyu UNSPECIFIED https://orcid.org/0000-0002-2191-3576 UNSPECIFIED Dao, Thien T.P. UNSPECIFIED https://orcid.org/0000-0002-5408-7442 UNSPECIFIED Wehrmann, Markus UNSPECIFIED https://orcid.org/0000-0001-7511-7471 UNSPECIFIED Lee, Hyun Ju UNSPECIFIED UNSPECIFIED UNSPECIFIED Vilchez, David UNSPECIFIED https://orcid.org/0000-0002-0801-0743 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-814370
Identification Number:	10.1016/j.celrep.2024.114626
Journal or Publication Title:	Cell Reports
Volume:	43
Number:	8
Page Range:	pp. 1-25
Number of Pages:	25
Date:	August 2024
Publisher:	Elsevier
ISSN:	2211-1247
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
Uncontrolled Keywords:	Keywords Language amyotrophic lateral sclerosis ; FUS ; stress granules ; proteostasis ; protein aggregation ; neurodegeneration ; PARylation ; PARP1 ; histone H1.2 English
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/81437