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

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

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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 [POLDIP3] 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.

Item Type:Doctoral Thesis
ID Code:11863
Contributors:Crosio, Claudia
Publisher:Universita' degli studi di Sassari
Uncontrolled Keywords:ALS, TDP-43, Epigenetic
Subjects:Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Divisions:001 Università di Sassari > 01-a Nuovi Dipartimenti dal 2012 > Scienze Biomediche
Cicli, scuole e corsi:Ciclo 30 > Life sciences and biotechnologies > Biochimica, fisiologia e biologia molecolare
Deposited On:08 Jun 2018 09:16

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