TDP-43 pathology is a disease hallmark that characterizes both sporadic and familial amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). TDP-43 has been implicated in transcription, RNA metabolism and transport, and different TDP-43 post-translational modifications, spanning from phosphorylation to acetylation, can regulate its activity. In the present PhD thesis we provide evidences that TDP-43 interacts with histone deacetylase 1 (HDAC1), both in vivo and in vitro. By biochemical assays, performed in SH-SY5Y cells, we demonstrated that HDAC1, as well as HDAC6, can modify TDP-43 acetylation, that occurs mainly on amino acid residues K142 and K192, located in the RRM1 and RRM2 domains, necessary for the interaction . Interestingly, HDAC1 overexpression modulates TDP-43 transcriptional activity on CHOP promoter, but not TDP43 splicing activity on polymerase delta interacting protein 3 [POLDipartimento di Chimica e Farmacia] gene. Finally, both in cell culture and in Drosophila, HDCA1 reduced level (genomic inactivation or siRNA) or treatment with pan-HDAC inhibitors, reduce WT or pathological mutant TDP-43 toxicity, suggesting TDP-43 acetylation as a new potential therapeutic target.

Epigenetics and neurodegeneration: physiological relevance of TDP-43/HDAC1 interaction / Sanna, Simona. - (2018).

Epigenetics and neurodegeneration: physiological relevance of TDP-43/HDAC1 interaction

SANNA, Simona
2018-01-01

Abstract

TDP-43 pathology is a disease hallmark that characterizes both sporadic and familial amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). TDP-43 has been implicated in transcription, RNA metabolism and transport, and different TDP-43 post-translational modifications, spanning from phosphorylation to acetylation, can regulate its activity. In the present PhD thesis we provide evidences that TDP-43 interacts with histone deacetylase 1 (HDAC1), both in vivo and in vitro. By biochemical assays, performed in SH-SY5Y cells, we demonstrated that HDAC1, as well as HDAC6, can modify TDP-43 acetylation, that occurs mainly on amino acid residues K142 and K192, located in the RRM1 and RRM2 domains, necessary for the interaction . Interestingly, HDAC1 overexpression modulates TDP-43 transcriptional activity on CHOP promoter, but not TDP43 splicing activity on polymerase delta interacting protein 3 [POLDipartimento di Chimica e Farmacia] gene. Finally, both in cell culture and in Drosophila, HDCA1 reduced level (genomic inactivation or siRNA) or treatment with pan-HDAC inhibitors, reduce WT or pathological mutant TDP-43 toxicity, suggesting TDP-43 acetylation as a new potential therapeutic target.
2018
ALS; TDP-43; Epigenetic
Epigenetics and neurodegeneration: physiological relevance of TDP-43/HDAC1 interaction / Sanna, Simona. - (2018).
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11388/250390
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