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.

HDAC1 inhibition ameliorates TDP-43-induced cell death in vitro and in vivo / Sanna, S.; Esposito, S.; Masala, A.; Sini, P.; Nieddu, G.; Galioto, M.; Fais, M.; Iaccarino, C.; Cestra, G.; Crosio, C.. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 11:5(2020), p. 369. [10.1038/s41419-020-2580-3]

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

Esposito S.
Membro del Collaboration Group
;
Nieddu G.
Membro del Collaboration Group
;
Galioto M.
Membro del Collaboration Group
;
Iaccarino C.
Conceptualization
;
Crosio C.
Conceptualization
2020

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.
HDAC1 inhibition ameliorates TDP-43-induced cell death in vitro and in vivo / Sanna, S.; Esposito, S.; Masala, A.; Sini, P.; Nieddu, G.; Galioto, M.; Fais, M.; Iaccarino, C.; Cestra, G.; Crosio, C.. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 11:5(2020), p. 369. [10.1038/s41419-020-2580-3]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11388/235644
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