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Study identifies possible mechanism
for brain damage in Huntington's disease
Mutant huntingtin protein may block
production of factor key to energy metabolism
BOSTON - October 5, 2006 - Researchers from the MassGeneral
Institute for Neurodegenerative Disease (MIND) have identified
a possible mechanism underlying how the gene mutation that causes
Huntington's disease (HD) leads to the degeneration and death of
brain cells. In the Oct. 6 issue of Cell, they show that
the abnormal form of the huntingtin protein, the product of the
HD gene mutation, interferes with the production of a protein critical
to cellular energy metabolism. The discovery is the first to bring
together two processes believed to be involved in the pathology
of HD - the conversion of genetic information into proteins and
the production of energy within cells.
"Our study indicates that these two pathogenic mechanisms are
linked, in that disruption of gene transcription by mutant huntingtin
leads to abnormal energy metabolism, which affects energy-dependent
cellular processes and results in neurodegeneration," says
Dimitri Krainc, MD, PhD, of MIND and the MGH Department of Neurology,
who led the research team. "The role of mitochondria [subcellular
structures that produce the cells' energy] in the process of nerve
cell dysfunction and death is an emerging theme in neurodegenerative
disorders, but the mechanism behind HD has been elusive."
HD causes the degeneration and death of cells in the basal ganglia
- an area deep within the brain - particularly in a structure called
the striatum. Although the precise function of the huntingtin protein
is still unknown, recent studies have suggested that the mutant
form directly interferes with transcription of neuronal genes. Evidence
also has pointed to disruptions in cellular energy metabolism as
key factors in HD. As a result, the MIND team focused on a protein
called PGC-1a, which is known to regulate energy in cells throughout
the body. Their previous research had shown that mice in which the
PGC-1a gene had been knocked out developed brain lesions in the
striatum.
To investigate the possible effect of the HD mutation on PGC-1a,
the researchers first examined brain tissue samples from presymptomatic
HD patients and found that levels of the protein were significantly
reduced in the portion of the striatum first affected by the disorder.
Examination of the brains of PGC-1a knockout mice found decreased
activity in metabolic pathways known to be involved in mitochondrial
function - pathways also downregulated in human HD - and brain samples
from HD patients also showed reduced expression of mitochondrial
genes.
Within the striatum HD causes degeneration of medium spiny neurons,
the most common cells within the structure. The reseachers found
that PGC-1a levels in those particular neurons were much lower among
mice with the HD mutation than in normal mice. In contrast, levels
of the protein were dramatically higher in striatal cells not affected
by HD, suggesting that PGC-1a may protect against neurodegeneration.
Analysis of striatal cells from the HD mice also showed significant
underexpression of both PGC-1a and key mitochondrial genes, further
linking decreased protein levels with deficits in energy metabolism.
Additional experiments indicated that mutant huntingtin interferes
with the production of PGC-1a by occupying the regulatory region
of the PGC-1a gene and inhibiting its transcription. Delivery of
a viral vector expressing PGC-1a into the striatum of mice with
the HD mutation resulted in significantly less degeneration of neurons
that expressed the injected PGC-1a than of other striatal cells,
suggesting that it may be possible to restore the protein's protective
effects.
"Our work provides specific, mechanistic evidence that energy
deficits contribute to neuro-degeneration in HD and suggests that
enhancing energy production in the brain may be neuroprotective.
We are beginning to search for new compounds that could correct
PGC-1a dysregulation and potentially reverse the disruption of energy
metabolism in HD," says Krainc, who is an assistant professor
of Neurology at Harvard Medical School.
Co-authors of the Cell paper are lead author Libin Cui, PhD,
Hyunkyung Jeong, MS, and Fran Borovecki, MD, PhD, of MGH Neurology;
and Christopher Parkhurst and Naoko Tanese, PhD, of New York University
School of Medicine. The research was supported by grants from the
National Institutes of Health and a Fulbright fellowship.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of nearly $500 million and
major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, transplantation biology and photomedicine. MGH and Brigham
and Women's Hospital are founding members of Partners HealthCare
HealthCare System, a Boston-based integrated health care delivery
system.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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