Increased transcription of transglutaminase 1 mediates neuronal death in in vitro models of neuronal stress and Aβ1–42-mediated toxicity

Neurobiology of Disease

Manuela Basso¹  Federica Costa²  Alice Migazzi²  Pamela Gatto²  Alessandro Roncador²  Debasmita Tripathy²  Lucia Boeri³  Mario Salmona⁴  Laura Colombo⁴  Diego Albani⁵  Federica Fusco⁵  Maria Pennuto⁶  Carlo Musio⁷  J. Leon Juárez-Hernández⁷  M.M. Micha Wilhelmus⁸  Benjamin Drukarch⁸ 

[1] Department of Biomedical sciences, via Ugo Bassi 58/B, University of Padova, 35131 Padova, Italy;Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Trento, TN, Italy;Department of Chemistry, Materials and Chemical Engineering “G. Natta”, Politecnico di Milano, Milan, Italy;Department of Molecular Biochemistry and Pharmacology, Laboratory of Biochemistry and Protein Chemistry, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy;Department of Neuroscience, Laboratory of Genetics of Neurodegenerative Disorders, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy;Dulbecco Telethon Institute Lab of Neurodegenerative Diseases, Centre for Integrative Biology (CIBIO), University of Trento, Italy;Institute of Biophysics, Trento Unit, National Research Council (IBF-CNR), Bruno Kessler Foundation (FBK), LabSSAH, Via alla Cascata 56/C, 38123 Trento, Italy;VU University Medical Center, Neuroscience Campus Amsterdam, Department of Anatomy and Neurosciences, Amsterdam, the Netherlands;

关键词: Transglutaminase 1;    Alzheimer's disease;    Aβ 1–42 peptides;    Neuronal death;    Activator protein 1;   

DOI  :  

来源: DOAJ

【 摘 要 】

Alzheimer's disease (AD) is the most common cause of dementia. At the pre-symptomatic phase of the disease, the processing of the amyloid precursor protein (APP) produces toxic peptides, called amyloid-β 1–42 (Aβ 1–42). The downstream effects of Aβ 1–42 production are not completely uncovered. Here, we report the involvement of transglutaminase 1 (TG1) in in vitro AD models of neuronal toxicity. TG1 was increased at late stages of the disease in the hippocampus of a mouse model of AD and in primary cortical neurons undergoing stress. Silencing of TGM1 gene was sufficient to prevent Aβ-mediated neuronal death. Conversely, its overexpression enhanced cell death. TGM1 upregulation was mediated at the transcriptional level by an activator protein 1 (AP1) binding site that when mutated halted TGM1 promoter activation. These results indicate that TG1 acts downstream of Aβ-toxicity, and that its stress-dependent increase makes it suitable for pharmacological intervention.

【 授权许可】

Unknown