Misbehaving Molecules: 3-Dimensional Pictures of ALS Mutant Proteins Support Two Major Theories About How the Disease is Caused
A new study reveals for the first time how gene mutations lead
to the inherited form of amyotrophic lateral sclerosis (ALS), or
Lou Gehrig's disease. The study suggests that the two most prominent
theories of how familial ALS (FALS) and other related diseases develop
are both right in part.
"No one has ever demonstrated at the molecular
level how ALS mutations might lead to disease," says study author
John Hart, Ph.D., director of the University of Texas Health Science
Center X-ray Crystallographic Core Laboratory in San Antonio. "Using
a technique commonly used in structural biology, we could see the
intimate details of how toxic familial ALS proteins interact. And
we found out that the proteins are interacting in a way they shouldn't
be." The study was funded by the National Institute of Neurological
Disorders and Stroke and appears in the June 2003 issue of Nature
ALS is a progressive, fatal neurological disease
that usually strikes in mid-life. It causes muscle weakness, leads
to paralysis, and usually ends in death within 2 to 5 years of diagnosis.
Affecting as many as 20,000 Americans, ALS occurs when specific
nerve cells in the brain and spinal cord that control voluntary
movement gradually degenerate.
About 10 percent of ALS cases are
familial ALS. Only one parent needs to have FALS to pass it on to
his or her children, although men are about one-and-a-half times
more likely to develop the disease than women. Studies that reveal
how FALS develops may give researchers new clues about the other
90 percent of ALS cases known as sporadic ALS and other neurodegenerative
diseases, such as Alzheimer's, Parkinson's, and Huntington's diseases.
Scientists studying FALS patients have identified more than 90 mutations
in the gene that directs the production of the protein copper-zinc
superoxide dismutase (SOD1). In FALS, proteins accumulate in a way
they shouldn't to form large protein complexes. Scientists believe
these complexes interfere with nerve cell transport, cellular waste
management, and other cellular activities that prevent cell death.
Similar large protein complexes have been implicated in other neurodegenerative
Using a 3-dimensional imaging technique called x-ray crystallography,
Dr. Hart and his colleagues compared the interactions among proteins
in the FALS mutant protein complexes to interactions among normal
Normally, proteins protect themselves from sticking to
one another by covering their edges with loop-shaped ends. The researchers
found that in the mutant proteins, the loops were in the wrong position.
This loss of protection appears to lead to the toxic accumulation
of proteins in FALS. The finding reveals a new mechanism for researchers
to exploit in their efforts to find ways to prevent or treat neurodegenerative
For years scientists have speculated about the disease
mechanisms in ALS. Researchers initially thought that the FALS mutation
in SOD1 led to a decrease in SOD1 activity and subsequent oxidative
damage to cells. But a recent study disproved the idea, showing
that mice completely lacking SOD1 lived to adulthood without developing
movement disorders. Mice with the human FALS -SOD1 mutation, however,
became paralyzed despite normal SOD1 levels.
Scientists now have
two primary theories for why the mere presence of the mutant SOD1
protein seems to cause FALS without interfering with SOD1 activity.
The new oxidative damage theory holds that mutant SOD1 proteins
produce chemicals called oxidants that damage and kill cells. In
a nutshell, the SOD1 protein needs to bind to a reactive metal in
order to form loops to protect its edges. The oxidants, however,
often damage the mutant SOD1 protein itself, interfering with metal
binding and leaving the protein unprotected.
The aggregation theory,
on the other hand, maintains that mutant SOD1 proteins fold improperly,
causing them to stick together and form large toxic protein complexes.
Researchers believe that those protein complexes interfere specifically
with transport machinery within the nerve cells that control voluntary
A recently substantiated addition to the aggregation theory,
suggested by studies in Parkinson's and Alzheimer's Diseases, is
that pore-like precursors of the protein aggregates not the aggregates
themselves may be killing the nerve cells. In this study, Dr.
Hart and Dr. Samar Hasnain saw those helical, pore-like precursors
using x-ray crystallography, providing striking evidence implicating
the aggregation theory in ALS.
"Our study provides a model for how
protein aggregation in FALS occurs," says Dr. Hart. "But it also
suggests that deadly oxidative chemistry can lead to metal loss
which in turn can lead to aggregation. These are very exciting findings,
because we have 3-D pictures that support two separate hypotheses."
These findings offer a unique contribution to the enormous effort
to understand not only the causes of, but also the possible ways
to treat or prevent FALS and other neurodegenerative disorders.
"If we can understand what is going on at the molecular level, we
may eventually be able to develop a drug to prevent the defect that
leads to disease," says study co-author Jennifer Stine Elam, a graduate
student in Dr. Hart's laboratory.
The NINDS is a component of the
National Institutes of Health within the Department of Health and
Human Services and is the nation's primary supporter of biomedical
research on the brain and nervous system.
This release will
be posted on EurekAlert! at http://www.eurekalert.org and on the
NINDS website at http://www.ninds.nih.gov/news