John I. Clark

clarkji@u.washington.edu
Professor and Chair, Department of Biological Structure

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Protein – protein interactions are the biophysical basis for cellular transparency, the fundamental characteristic of lens fiber cells. With aging and post-translational modification, abnormal protein – protein interactions result in aggregation and loss of lens cell transparency. The aggregation process in the aging lens resembles amyloid formation in the aging brain. The accessibility of the lens in the living animal provides a unique opportunity to study interactions between proteins in vivo which result in protein aggregation or amyloid formation. Like the brain, the early development of the lens begins in the cranial ectoderm of the trilaminar embryo. Lens formation is initiated when surface cells elongate in response to the optic vesicle, an outgrowth from the forebrain. From the very earliest stages of cell differentiation, common transcription factors, cell adhesion molecules, channel proteins, cytoskeletal elements, and regulatory molecules contribute to the development of the lens, major sensory organs, and ganglia connected to the brain. Similar to the brain, the lens contains amyloid precursor protein (APP), amyloid beta (Abeta), tau, beta secretase, presenilin and alpha synuclein which are associated with neurodegeneration. The alpha crystallins are stress proteins, concentrated in lens to provide protection against partial unfolding mechanisms that can result in protein aggregation. This laboratory utilizes recombinant expression of proteins, site directed mutagenesis and transgenic animals in the investigation of the molecular and cellular basis for lens cell transparency in normal aging and in association with neurodegenerative diseases including Alzheimer’s, Parkinson’s and Huntington’s diseases. Quantitative techniques of protein biochemistry, molecular biology, LASER light scattering spectroscopy and light and electron microscopy are used to characterize the protective mechanisms against protein unfolding/misfolding and aggregation during molecular aging in the lens or brain. Novel technology and instrumentation are being developed by students who worked in this laboratory, nearly all of whom are co-inventors on patents.