ALS-FUS mutations cause abnormal PARylation and histone H1.2 interaction, leading to pathological changes
Hafiza Alirzayeva,
Rute Loureiro,
Seda Koyuncu,
Franziska Hommen,
Yara Nabawi,
William Hongyu Zhang,
Thien T.P. Dao,
Markus Wehrmann,
Hyun Ju Lee,
David Vilchez
Affiliations
Hafiza Alirzayeva
Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
Rute Loureiro
Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
Seda Koyuncu
Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
Franziska Hommen
Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
Yara Nabawi
Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
William Hongyu Zhang
Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
Thien T.P. Dao
Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
Markus Wehrmann
Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
Hyun Ju Lee
Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
David Vilchez
Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Institute for Genetics, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany; Corresponding author
Summary: 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.
