TY  - JOUR
AU  - Yazar, Volkan
AU  - Kühlwein, Julia
AU  - Knehr, Antje
AU  - Grozdanov, Veselin
AU  - Ekici, Arif B
AU  - Ludolph, Albert C
AU  - Danzer, Karin M
TI  - Impaired ATF3 signaling involves SNAP25 in SOD1 mutant ALS patients.
JO  - Scientific reports
VL  - 13
IS  - 1
SN  - 2045-2322
CY  - [London]
PB  - Macmillan Publishers Limited, part of Springer Nature
M1  - DZNE-2023-00746
SP  - 12019
PY  - 2023
AB  - Epigenetic remodeling is emerging as a critical process for several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Genetics alone fails to explain the etiology of ALS, the investigation of the epigenome might therefore provide novel insights into the molecular mechanisms of the disease. In this study, we interrogated the epigenetic landscape in peripheral blood mononuclear cells (PBMCs) of familial ALS (fALS) patients with either chromosome 9 open reading frame 72 (C9orf72) or superoxide dismutase 1 (SOD1) mutation and aimed to identify key epigenetic footprints of the disease. To this end, we used an integrative approach that combines chromatin immunoprecipitation targeting H3K27me3 (ChIP-Seq) with the matching gene expression data to gain new insights into the likely impact of blood-specific chromatin remodeling on ALS-related molecular mechanisms. We demonstrated that one of the hub molecules that modulates changes in PBMC transcriptome in SOD1-mutant ALS patients is ATF3, which has been previously reported in an SOD1G93A mouse model. We also identified potential suppression of SNAP25, with impaired ATF3 signaling in SOD1-mutant ALS blood. Together, our study shed light on the mechanistic underpinnings of SOD1 mutations in ALS.
KW  - Animals
KW  - Mice
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Leukocytes, Mononuclear: metabolism
KW  - Mice, Transgenic
KW  - Mutation
KW  - Superoxide Dismutase: genetics
KW  - Superoxide Dismutase: metabolism
KW  - Superoxide Dismutase-1: genetics
KW  - Superoxide Dismutase (NLM Chemicals)
KW  - Superoxide Dismutase-1 (NLM Chemicals)
KW  - SNAP25 protein, human (NLM Chemicals)
KW  - SOD1 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC10368635
C6  - pmid:37491426
DO  - DOI:10.1038/s41598-023-38684-8
UR  - https://pub.dzne.de/record/259245
ER  -