Misfolded and damaged proteins are common to all human neurodegenerative diseases. Clumps of these aggregated proteins destroy neurons within the brain and cause disease. But explanations for the mechanism that actually causes cell death have varied widely, puzzling scientists and leading them to ask whether Alzheimer's, Parkinson's, Huntington's and Creutzfeldt-Jakob diseases and familial amyotrophic lateral sclerosis (ALS) are related diseases or very different diseases.
Northwestern University scientists now offer a clue that may get to the core of the cell death question and establish a common mechanism in these diseases. In a study to be published online Feb. 9 by the journal Science, the research team shows that polyglutamine (the toxic component of the protein responsible for Huntington's disease) is so demanding on the cell's system that it changes the environment within the cell, causing other metastable, or partially folded, proteins to crash and lose function. Over time, this can cause the organism to die.
"Our results suggest that these disease-associated, aggregation-prone proteins may exert their destabilizing effects by interfering generally with other proteins that are having difficulty folding," said Richard I. Morimoto, Bill and Gayle Cook Professor of Biochemistry, Molecular Biology and Cell Biology, who led the study. Morimoto is an expert in Huntington's disease and on the cellular and molecular response to damaged proteins.
"We found that the system for protein quality control is not robust at all -- it is very delicate," said Morimoto. "Slight changes in the cell's environment have huge consequences. A single mutant polyglutamine protein interferes with the folding and functioning of very different types of proteins in the cell. This, in turn, could interfere with innumerable cellular processes and offers an explanation of why so many different mechanisms have been proposed for toxicity and cell death."
Morimoto speculates that it could be the misfolded protein's structure that, indirectly, is causing the other proteins to become non-functional. If so, these findings have implications for all neurodegenerative diseases. For each disease, a single or a small number of mutant proteins have been identified as causing the disease, and studies have shown that the misfolded states of these mutant proteins are all structurally related.