Cellular levels of Grb2 and cytoskeleton stability are correlated in a neurodegenerative scenario

• Main Authors: Piyali Majumder, Kasturi Roy, Brijesh Kumar Singh, Nihar Ranjan Jana, Debashis Mukhopadhyay
• Format: Article
• Language: English
• Published: The Company of Biologists 2017-05-01
• Series: Disease Models & Mechanisms
• Subjects: Alzheimer's disease; APP/PS1 mouse model; Growth factor receptor bound protein 2; GRB2; Cytoskeleton; β-amyloid; β-amyloid protein precursor intracellular domain; AICD
• Online Access: http://dmm.biologists.org/content/10/5/655
• ISSN: 1754-8403; 1754-8411

Alzheimer's disease (AD) manifests as neuronal loss. On the premise of Grb2 overexpression in AD mouse brain and brain tissues of AD patients, our study primarily focuses on the stability of cytoskeletal proteins in the context of degenerative AD-like conditions. Two predominant molecular features of AD, extracellular accumulation of β-amyloid oligomers and intracellular elevation of amyloid precursor protein intracellular domain levels, have been used to closely inspect the series of signalling events. In their presence, multiple signalling pathways involving ROCK and PAK1 proteins lead to disassembly of the cytoskeleton, and Grb2 partially counterbalances the cytoskeletal loss. Increased Grb2-NOX4 interactions play a preventive role against cytoskeletal disassembly, in turn blocking the activity of nitrogen oxides and decreasing the expression of slingshot homolog 1 (SSH-1) protein, a potent inducer of cytoskeleton disassembly. This study unravels a unique role of Grb2 in protecting the cytoskeletal architecture in AD-like conditions and presents a potential new strategy for controlling neurodegeneration.