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.

The experiments were conducted in C. elegans, a transparent
roundworm whose biochemical environment is similar to that of human
beings and whose genome, or complete genetic sequence, is known. The
researchers picked seven random and unrelated proteins that are
expressed in the same compartment in the cell as mutant
polyglutamine. The seven metastable proteins -- each essential to
the functioning of muscle, nerve or hypodermal cells -- had a
temperature-sensitive mutation: the proteins are fine at normal
temperature but when the temperature is elevated the mutation is
expressed.

When the researchers introduced the toxic polyglutamine protein, the
environment of the cell completely changed. In the case of each of
the seven proteins, the presence of the expanded polyglutamine
caused each mutation to be expressed at normal temperature. In turn,
the metastable protein intensified the aggregation properties of the
polyglutamine protein.

"These results could provide a very powerful tool for understanding
all the neurodegenerative diseases," said Morimoto. "Do all proteins
that cause this class of disease, such as mutant SOD in familial ALS
or prions in Creutzfeldt-Jakob disease, have the same consequences?
To find out, we plan to do the same experiments using the mutant
proteins associated with the other diseases."

"This research suggests that a common mechanism may underlie a
variety of protein folding diseases," said James Anderson, a
geneticist at the National Institute of General Medical Sciences, at
the National Institutes of Health, which partially funded the
research. "While the hypothesis needs to be tested in other
organisms, findings made in model organisms such as C. elegans are
often the first step in understanding the molecular roots of human
diseases."

In addition to Morimoto, other authors on the Science paper are post-
doctoral fellows Tali Gidalevitz and Anat Ben-Zvi (co-first
authors), undergraduate student Kim Ho, and recent Ph.D. recipient
Heather R. Brignull, all from Northwestern University.

Megan Fellman
fellman@...
Northwestern University
http://www.northwestern.edu

.