July 13, 2000
A New Model of Cell Death in Neurodegenerative Disease
Researchers at the University of Toronto have discovered a common
principle underlying the death of brain cells in a number of
neurodegenerative disorders, including retinal degeneration,
Parkinson’s and Huntington’s diseases. The scientists have
shown that rather than gradually growing sicker and dying, neurons
succumb to a single, rare catastrophic event that causes the cells to
die randomly during the course of the disease.
The finding challenges commonly held assumptions about how and when
nerve cells die as a result of neurodegenerative disorders. Many
researchers had favored the "cumulative-damage hypothesis," which
states that the death of specific types of neurons is caused by a
buildup of damage sustained over time.
“It took us months and months to think about what a constant risk of cell death might mean”
Roderick R. McInnes
In an article in the July 13, 2000, issue of the journal
Nature, HHMI international research scholar Roderick R. McInnes
at the Hospital for Sick Children, working with colleagues at the
University of Toronto and the University of British Columbia, reports
evidence for a "one-hit" model of cell death in 15 different examples
of neurodegenerative disease.
According to the model, the mutant brain cells work well for years
or decades even though they are at a constant risk of death. The
researchers believe that the one-hit hypothesis can explain neuronal
death in a wide variety of settings, including photoreceptor
degeneration, excitotoxic cell death of hippocampal neurons, a mouse
model of cerebellar degeneration, Parkinson’s and
Huntington’s diseases.
The path to the discovery began when McInnes and his colleagues
knocked out a mouse gene, ROM-1, that is essential for
photoreceptor cells in the retina. As expected, the mouse
photoreceptors died. (In humans, a similar mutation causes retinitis
pigmentosa, a form of retinal degeneration). The rate of cell death in
the mouse photoreceptor population did not seem quite right, if
cumulative damage was occurring. In most neurodegenerative diseases,
scientists expect to see larger numbers of cells die as the disease
progresses. This massive die-off of cells later in disease is one of
the hallmark predictions of the cumulative damage hypothesis.
But the mouse cells in McInnes’s lab defied the cumulative
damage pattern. Instead, the proportion of photoreceptors that died
remained constant at all times, indicating that their risk of death is
constant. "It took us months and months to think about what a constant
risk of cell death might mean," McInnes says.
Scanning the scientific literature, the team found similar cell
death rates in data from 15 different neurodegenerative diseases —
hinting that a common biochemical principle drives these vastly
different disorders. The scientists suggest that in each case, a
disease-causing mutation or toxic insult upsets the biochemical balance
in the affected brain cells. As long as the biochemical balance stays
close to its normal range, the cell carries on perfectly well. But when
the balance is randomly tipped in one direction, the mutant cell
activates a genetic program that causes cell death.
"The new model shows that every once in a while, you can take a hard
look at existing data and make a profound discovery," said Harvard
University geneticist Thaddeus Dryja. "This finding has been staring
science in the face for decades. The exponential declines in cell death
in neurodegenerative disease are not a secret — it’s just that
nobody has really stopped to think through what they mean for
biology."
If the one-hit model is correct, McInnes says, it may mean that
neurons affected by Parkinson’s disease, for example, are not
necessarily doomed. The right drug could reverse the critical chemical
imbalance caused by a mutation, returning the cells to a normal state.
"That’s a lot less catastrophic than assuming a disease slowly
causes the whole cell to fall apart," he says. The challenge, he adds,
will be in identifying the precise chemical reactions — and underlying
mutations—that cause each neurodegenerative disease.
"That’s no easy task," McInnes admits. "But maybe we’re one
step closer now."
|
