New Insights to Clathrin and Adaptor Protein 2 for the Design and Development of Therapeutic Strategies

International Journal of Molecular Sciences

Ebbe Toftgaard Poulsen¹  Agnete Larsen²  Alen Zollo²  Arne L. Jørgensen²  Kristian W. Sanggaard¹  Jan J. Enghild¹  Carmela Matrone² 

[1] Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej, 10C, Aarhus 8000, Denmark;Institute of Biomedicine, Aarhus University, Bartholins Alle’, 6, Aarhus 8000, Denmark;

关键词: Clathrin heavy chain;    APP;    ₆₈₂YENPTY₆₈₇;    AICD;    AP-2;    Alzheimer’s disease;   

DOI  :  10.3390/ijms161226181

来源: mdpi

【 摘 要 】

The Amyloid Precursor Protein (APP) has been extensively studied for its role as the precursor of the β-amyloid protein (Aβ) in Alzheimer’s disease (AD). However, our understanding of the normal function of APP is still patchy. Emerging evidence indicates that a dysfunction in APP trafficking and degradation can be responsible for neuronal deficits and progressive degeneration in humans. We recently reported that the Y₆₈₂ mutation in the ₆₈₂YENPTY₆₈₇ domain of APP affects its binding to specific adaptor proteins and leads to its anomalous trafficking, to defects in the autophagy machinery and to neuronal degeneration. In order to identify adaptors that influence APP function, we performed pull-down experiments followed by quantitative mass spectrometry (MS) on hippocampal tissue extracts of three month-old mice incubated with either the ₆₈₂YENPTY₆₈₇ peptide, its mutated form, ₆₈₂GENPTY₆₈₇ or its phosphorylated form, ₆₈₂pYENPTY₆₈₇. Our experiments resulted in the identification of two proteins involved in APP internalization and trafficking: Clathrin heavy chain (hc) and its Adaptor Protein 2 (AP-2). Overall our results consolidate and refine the importance of Y₆₈₂ in APP normal functions from an animal model of premature aging and dementia. Additionally, they open the perspective to consider Clathrin hc and AP-2 as potential targets for the design and development of new therapeutic strategies.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.