Northwestern University scientists have made a key molecular discovery that has implications for a wide range of diseases characterized by the loss of nerve function, including Alzheimer's, Huntington's, Parkinson's, and Lou Gehrig's diseases, cystic fibrosis, and Creutzfeldt-Jakob disease, the human form of mad cow disease.
The findings, which are published in the October 1 issue of Nature Cell Biology, could lead to an understanding of how to prevent these diseases and to the development of effective drugs.
All human neurodegenerative diseases have two things in common. First, misfolded and damaged proteins clump together to form toxic species that aggregate, destroy cell function and cause disease. Second, studies have shown that special protective proteins, called molecular chaperones, can suppress these toxic effects. This question remained: How do the chaperones and aggregates interact with each other?
A research team led by Richard I. Morimoto, PhD, John Evans Professor of Biology, now can answer that question. The researchers have become the first to view, in living cells and in real time, the interactions between the beneficial molecular chaperone Hsp70 and the damaging protein aggregate, shedding light on how the chaperone works to minimize aggregate growth.
"We now understand how the chaperone influences the aggregate's toxic effect on the cell," said Dr. Morimoto. "We observed that the chaperone is binding to and then coming off the aggregate all the time. This dynamic relationship is unusual because the aggregate, the result of a genetic mutation, brings healthy and otherwise normal proteins to aggregate irreversibly with them. But this clearly is not the case with the molecular chaperone."
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Instead, the molecular chaperone is allowed, for reasons not fully understood, to do its work preventing healthy proteins essential to cell function from being bound to the aggregate, a biochemical "black hole." The chaperone is continually sampling the aggregate to see what's there and to release any healthy proteins from the aggregate's clutches. This could suppress the aggregate's growth, prolonging the life of the cell and delaying the onset of disease.
"These observations provide the first visual study of this cell survival activity," said Dr. Morimoto, whose team studied the chaperone Hsp70 (a heat shock protein) and polyglutamine aggregates, the type of protein aggregate responsible for Huntington's disease. "The molecular chaperones are not like other proteins."
In order to visualize the behavior of chaperones and aggregates in an animal, the researchers use human tissue culture cells and C. elegans , a transparent roundworm whose biochemical environment is similar to that of human beings and whose genome, or complete genetic sequence, is known.
Although the Northwestern researchers are studying Huntington's disease, these experimental models can be used to study other neurodegenerative diseases because of the common molecular components.
Proteins, made up of different combinations of amino acids, are basic components of all living cells. To do its job properly, each protein first must fold itself into the proper shape. In this process, the protein receives its folding instructions from its amino acid sequence and is assisted by a class of proteins known as heat shock proteins or molecular chaperones that function to prevent misfolding, or, in the case of already misfolded proteins, to detect them and prevent their further accumulation.
In Huntington's disease, for example, a mutated gene directs production of a protein with an increasing number of consecutive residues of the amino acid glutamine. When the number of residues expands past 40, the protein exhibits unusual biochemical properties, causing the protein to misfold. This results in a loss of function and protein aggregation — in other words, disease.
"How do we use this new information about molecular chaperones to our advantage, to protect individuals from the molecular damage of disease?" said Dr. Morimoto. "That is our next challenge."