Researchers at Johns Hopkins and the University of
Minnesota have discovered a gene mutation in the
descendants of Abraham Lincoln's grandparents that suggests
the Civil War president himself might have also suffered
from a disease that destroys nerve cells in the cerebellum,
the part of the brain that controls movement. A report on
this discovery will appear in the February print issue of
Nature Genetics.
The joint finding of the SCA5 mutation comes more than
a decade after initial speculation that Lincoln might have
suffered from Marfan disease. People with this inherited
disorder are often tall and thin and can commonly have
slender, tapering fingers. The identification of the Marfan
gene at Johns Hopkins in 1991 sparked debate concerning
testing of President Lincoln's DNA to determine whether his
tall stature could have been caused by that disease.
The present discovery in descendants of Lincoln's
grandparents of the gene that causes a movement disorder
called spinocerebellar ataxia type 5, however, appears to
offer much stronger evidence that the past president
himself might have had SCA5, according to Jeffrey D.
Rothstein, a professor of
neurology and
neuroscience and vice chairman for research in the
Department of Neurology at the Johns Hopkins School of
Medicine. SCAs are neurodegenerative disorders that cause
loss of coordination of limbs and eye movements, slurred
speech and swallowing difficulties.
"Determining President Lincoln's status relative to
SCA5 would be of historical interest and would increase
public awareness of ataxia and neurodegenerative disease,"
Rothstein said. The finding also has wider implications
because similar mutations might also be associated with
other neurodegenerative diseases, he said.
The researchers discovered that SCA5 is caused by a
mutation of the *-III spectrin gene SPTBN2, which disrupts
the ability of certain nerves in the cerebellum to respond
normally to incoming chemical signals. Eventually, these
nerves, called Purkinje cells, degenerate, and the person
loses fine control of the leg and arm muscles. This would
explain historical descriptions of Lincoln's uneven gait
— an early sign of ataxia — according to the
researchers. Ataxia is an inability to coordinate muscle
activity in the arms and legs.
"The discovery by the team of the SCA5 mutations in 90
of 299 descendants [of Lincoln's grandparents] could enable
us to prove whether Lincoln himself carried the mutation by
studying genetic material obtained from artifacts
containing his DNA," said Rothstein, a co-author of the
Nature Genetics paper.
The researchers found the mutation in all 90 affected
individuals (ages 7 to 80 at time of exam) and in 35
descendants who had not yet started to show symptoms of
SCA5 (ages 13 to 67 at time of exam), he said. The team
also found two other types of mutations in *-III spectrin
2, one in a French family and another in a German. The
mutations found in the American, French and German families
each affected a different part of the SPTBN2 gene and thus
knocked out a different part of the *-III spectrin
protein.
The mutation of the SPTBN2 gene disrupts the normal
shape of *-III spectrin, a protein that is key to the
proper functioning of Purkinje cells, according to
Rothstein, who cloned the protein in 2001 and first
described its role in the brain. Specifically, *-III
spectrin helps to anchor another protein, called glutamate
transporter EAAT4, into the membrane of the Purkinje
cell.
In the current study, the investigators showed in
isolated cells that EAAT4 tends to migrate rapidly through
the membrane of Purkinje cells. This movement disrupts the
ability of the nerve-signaling chemical glutamate to bind
with EAAT4, Rothstein said. "The loss of the ability of
*-III spectrin to anchor EAAT4 in place so it can respond
to glutamate could lead to signaling abnormalities over
time," Rothstein said. "And over time, that could cause
Purkinje cell death and lead to the symptoms of SCA5."
A further implication of these findings is that SCA5
mutations could affect the complex movement of proteins in
other nerve cells, the researchers said. Specifically, the
spectrin's interaction with a molecular "motor" that
shuttles proteins through the cell suggests that mutated
forms of this protein would disrupt this critical
function.
Along with glutamate transporters, the motor, which
transfers proteins along cellular highways called
microtubules, is implicated in a wide range of processes
that are key to proper functioning of nerves, Rothstein
noted. Disruption of the motor appears to occur in several
neurodegenerative diseases, including amyotrophic lateral
sclerosis, he added. ALS is a fatal disease involving the
cells in the brain and spinal cord that control muscles.
Motor disruption also occurs in Huntington's disease, a
genetic disorder that causes degeneration of brain cells in
certain areas of the brain, resulting in uncontrolled
movements, loss of intellectual abilities and emotional
disturbance. In addition, disruption of protein transport
through the long arms of nerves called axons occurs in
Alzheimer's disease, he added.
"The results of our work and that of other researchers
suggest that even though different *-III spectrin mutations
disrupt different cellular processes, all of these
different disruptions eventually cause the death of a
particular brain cell," he said. "So further studies of
SCA5 will likely provide insight into molecular mechanisms
common to SCA5 and other neurodegenerative diseases. In
recent years we have discovered drugs that can modulate the
glutamate transporter and its gene, and that research could
someday be useful for treating patients with
spinocerebellar ataxia."
The paper's senior author is Laura Ranum, of the
University of Minnesota. Dan Gincel of Johns Hopkins is
also an author.
This work was funded in part by the Programme
Hospitalier de Recherche Clinique, Verum Foundation,
European Community (EUROSCA integrated project), National
Ataxia Foundation, Bob Allison Ataxia Research Center,
Minnesota Medical Foundation and the National Institutes of
Health.