Amyloid Oligomers and Functional Amyloids
Because of their prevalence in protein misfolding diseases, amyloid fibrils were initially suspected to be cytotoxic and pathogenic, which stimulated intensive research efforts on amyloid fibrils for several decades. More recent studies on Abeta42—an isoform of amyloid-beta—and others, however, suggest that cytotoxicity more directly relates to the soluble oligomers that form during amyloid fibrillization. The kinetic and thermodynamic properties of amyloid oligomers are completely different from those of amyloid fibrils, so are their interactions with neurons. Characterization of these oligomers from each precursor (e.g., Abeta in Alzheimer’s disease and alpha-syn in Parkinson’s disease) is, unfortunately, not straightforward because they form many different and transient multimeric structures over time scales that are incompatible with common analytical methods. We are trying to discover methodologies to study the kinetics of the formation of amyloid oligomers.
Some amyloid fibril-based structures are not pathogenic, but rather beneficial. Representative examples include extracellular biofilm formation in bacteria, amyloid-templated biosynthesis of melanin in mammalian melanocytes. The biologically versatile nature of these structures, and their superior material properties (e.g., Young’s modulus and stiffness), make them useful in a broad range of applications. There have been a few examples of engineered fibril-based structures (e.g., scaffolds for cell adhesion, inorganic nanostructures, tethers for enzyme immobilization) but the design of amyloid structures with specific properties and/or functionalities (e.g., ion-capturing, molecule-binding, crystal templating) remains as a difficult goal, due to the incomplete understanding of the mechanisms governing their formation. To this end, we are developing ways to adopt/design amyloid structures for useful chemical functionalities, inspired by the nature’s ways.
Glyconeurochemistry
Glycosylation is the abundant, post-translational modification of mammalian proteomes, which adds diversity and complexity to protein functionality. The distribution and composition of diverse cell surface-glycans―as conjugated forms with proteins, lipids, or nucleic acids―contain much information regarding physiological states of the cell. In neurons, particularly, surface glycans are known to affect neurite development, synaptic plasticity, and regeneration. We use unnatural saccharide molecules as bioorganic handles with which we can specifically visualize a certain type of glycan and/or modulate its functions.
Neuron-Material Interfaces
Designing neuron-material interface—a space where neurons have physical/chemical interactions with an artificial surface—is a crucial part of generating in vitro neural network and performing fundamental research on neural cell biology. Chemistry has proven particularly useful for such purpose: surface organic chemistry helped to generate surfaces with biochemical or electrochecmial functions and nanochemistry enabled fabrication of neuro-active topographies. We are interested in designing neuron-material interfaces with advanced functions by utilizing new organic/nanochemistry strategies.
