HDAC1 inhibition ameliorates TDP-43-induced cell death in vitro and in vivo

• Published in: Cell death & disease 2020-05, Vol.11 (5), p.369-369, Article 369
• Main Authors: Sanna, Simona, Esposito, Sonia, Masala, Alessandra, Sini, Paola, Nieddu, Gabriele, Galioto, Manuela, Fais, Milena, Iaccarino, Ciro, Cestra, Gianluca, Crosio, Claudia
• Format: Article
• Language: English
• Subjects: 13/1; 14/19; 38/1; 38/109; 38/70; 38/89; 631/337/176; 631/378/1689/1285; 64/24; 82/29; Acetylation; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - pathology; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell death; Cell Death - drug effects; Cell Death - physiology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - pharmacology; Frontotemporal dementia; Frontotemporal Lobar Degeneration - metabolism; Frontotemporal Lobar Degeneration - pathology; FUS gene; Histone deacetylase; Histone Deacetylase 1 - genetics; Histone Deacetylase 1 - metabolism; Humans; Immunology; Inclusion Bodies - metabolism; Life Sciences; Mice; Mutation - genetics; Neurodegeneration; siRNA; Therapeutic applications; Toxicity; Transcription
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-2580-3

ABSTRACT TDP-43 pathology is a disease hallmark that characterizes both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). TDP-43 undergoes several posttranslational modifications that can change its biological activities and its aggregative propensity, which is a common hallmark of different neurodegenerative conditions. New evidence is provided by the current study pointing at TDP-43 acetylation in ALS cellular models. Using both in vitro and in vivo approaches, we demonstrate that TDP-43 interacts with histone deacetylase 1 (HDAC1) via RRM1 and RRM2 domains, that are known to contain the two major TDP-43 acetylation sites, K142 and K192. Moreover, we show that TDP-43 is a direct transcriptional activator of CHOP promoter and this activity is regulated by acetylation. Finally and most importantly, we observe both in cell culture and in Drosophila that a HDCA1 reduced level (genomic inactivation or siRNA) or treatment with pan-HDAC inhibitors exert a protective role against WT or pathological mutant TDP-43 toxicity, suggesting TDP-43 acetylation as a new potential therapeutic target. HDAC inhibition efficacy in neurodegeneration has long been debated, but future investigations are warranted in this area. Selection of more specific HDAC inhibitors is still a promising option for neuronal protection especially as HDAC1 appears as a downstream target of both TDP- 43 and FUS, another ALS-related gene.