Amyloids are formed by misfolded proteins that underlie a series of neurodegenerative diseases, including Alzheimer’s disease and systemic diseases including diabetes mellitus and cystic fibrosis. In a series of studies, using AFM, biochemical assays, cell physiology and cell biology we have now defined clearly that small oligomeric amyloidogenic peptides and not their fibrillar form induce toxicty by forming ion channels (J Biol Chem 1998, FASEB J, 2001, 2000., 2000, Biochemistry, 1999; PNAS 2005). Thus protein misfolding diseases belong to the so-called “channelopathies” with defined structural features that could be used to screen, design and deliver therapeutic interventions. In collaboration with Dr. Ruth Nussinov at NCI and at Tel Aviv University, we have now used atomistic scale molecular dynamic simulation to define why these amyloids form ion channels. The findings are published in TIBS (2007) and PNAS (2010).
Using AFM, we first showed that hemichannels exist naturally as an independent entity (Am. J. Physiol, 1995). We then showed that their 3D structure include pore region made of hydrophobic domains (JBC, 2005; Protein Data Bank), they are gated by physiological extracellular calcium activity (JBC, 20005; JCB, 2000), and serve an important physiological function: maintenance of normal cell volume and mechanics (JCB, 2000) and also regulate cell fate in oxidative stress and abnormal conditions (PLOS One, 2007). We are now taking a system biology approach to examine the signal transduction pathways underlying the abovementioned oxidative stress induced pathophysiology.