Huntington’s disease is one of many that continue to
present unanswered questions to researchers. UCLA Neuropsychiatric
Institute researchers, however, are beginning to make strides in
understanding the mechanism by which the perplexing disease
manifests itself among brain cells.
The theory to date has been that a genetic mutation in the
“Huntington protein” results in an abnormal
accumulation of the protein, forming aggregates in the brain. The
mutant protein subsequently destroys a group of brain cells.
William Yang and his fellow researchers at the UCLA
Neuropsychiatric Institute have proposed a new model in which the
Huntington protein also causes neighboring cells to exert adverse
effects in destroying brain cells. The research was published May 5
in Neuron, a neuroscience journal.
“Since neighboring cells usually don’t die in the
disease but they express the mutant protein, could they provide
pathological cell-cell interactions?” said Yang, assistant
professor at the UCLA Neuropsychiatric Institute and a member of
the Brain Research Institute.
Using two groups of mouse models, the team researched if
cell-cell interactions played a role in Huntington’s disease.
One group of mice was designed to generate Huntington protein
throughout the brain while a second group only produced the mutant
protein in target cells inclined to degeneration.
The mouse models showed that solely expressing the mutant
protein in target cells did not yield symptoms or pathological
characteristics of the disease, while expressing the protein
throughout the brain did.
“We have some evidence suggesting that cortical
interneurons may be the neighboring cells that provide such toxic
communications. … We found that the interneurons became abnormal
very early in the disease process and generate abnormal
communications to the pyramidal neurons.” Yang said.
Pyramidal cells, the target cells of the study, are
triangular-shaped neurons in the cerebral cortex, the outer layer
of the brain involved in thought processes and motor function.
Interneurons are the cells that regulate these pyramidal
neurons.
The research group, which also includes Xiaofeng Gu, Victor Lo,
Weizheng Wei and Istvan Mody of UCLA, has found that cell-cell
interactions are an integral aspect of how Huntington’s
disease fatally degenerates the brain.
“In order to get disease pathology you have to have the
Huntington protein expressed in a network of cells that are
interconnected,” said Istvan Mody, professor in the
department of neurology at the David Geffen School of Medicine.
Michael Levine, who has worked with Yang on the mouse models,
also conducts Huntington’s disease research that focuses on
cell-cell interactions and the hypothesis of excitotoxicity, which
explains neuron death. Excitotoxicity is usually based on glutamate
receptors which are involved in cell signaling.
“Either glutamate receptors are overly sensitive or too
much glutamate is possibly being released at the synapsis and cells
become overexcited and can’t survive this. In humans they
eventually die and in most mice models the cells become
dysfunctional and show signs of degeneration,” said Levine, a
professor in the Department of Psychiatry and Behavioral Science at
the David Geffen School of Medicine.
Levine is currently studying various drugs to see if these
effects can be reversed in mice.
The neuro-degenerative Huntington’s disease has a late
onset, but can affect children as well. Patients with the disease
have trouble moving and speaking, cognitive defects and psychiatric
symptoms. It is lethal within 10 to 25 years of onset.
Yang and his fellow researchers are currently trying to pinpoint
specific cells involved in producing toxic effects in the brain as
well as better understanding the molecular mechanisms of the
cell-cell interactions.
“The clinical prospects is not immediate. … It is very
important to understand the mechanism clearly and to understand
which cells are involved in Huntington’s disease,” Yang
said.