A ground-breaking new research approach to understanding the cellular processes of Alzheimer's and other degenerative diseases has revealed a promising pathway to the development of new types of drugs for these diseases.
The discovery, made in the laboratory of Ratnesh Lal, research scientist in the Neuroscience Research Institute (NRI) at the University of California, Santa Barbara, is published in this week's online issue of the Proceedings of the National Academy of Sciences (PNAS).
The research describes a new way of understanding the degeneration of brain cells in patients with Alzheimer's, Huntington's, and Parkinson's diseases, as well as other degenerative diseases. Misfolded proteins in the cell membrane, and subsequent changes in the electrical properties of cells, provide the explanation for the cell degeneration. Specific three-dimensional structures of misfolded proteins are embedded in the cell membrane.
"It has long been thought that amyloid plaque, which has been studied for 30 years, was the cause of Alzheimer's disease," said Lal. "Plaque isn't the cause." He explained that the fibers of plaque are too large to directly affect small cells.
The answers may come from small globs of misshapen, misfolded proteins that make well-defined holes in cell membranes and disrupt their electrical activity, according to the study.
Amyloid protein is a sticky, globular substance created when normal cellular proteins become twisted and contorted into abnormal shapes. While amyloid formation has been associated with diseases like Alzheimer's, Parkinson's, and Huntington's, scientists have puzzled over whether and how it actually kills cells and causes disease. To gain insight into this mysterious process, Lal and his research team examined the three-dimensional structure of several different proteins associated with these diseases. The researchers observed that all of the proteins folded into structures resembling ion channels, or pores within cell membranes. These pores control the electrical properties of the cell by regulating the flow of charged particles (ions) such as calcium.
When embedded into artificial membranes, the misfolded proteins were able to produce electrical currents, confirming their similarity to ion channels. Since abnormal ion balance is known to disrupt cell function and cause degeneration, these results provide proof of a possible mechanism by which amyloid formation may lead to the cellular destruction seen in these neurodegenerative diseases.