有关LB作用的重要文献
2007-12-30 15:31阅读：
周三下午的读书报告上，童彤给大家讲了有关LB的组分、作用以及生化病理的相关内容，大家对LB的作用到底是保护性，还是毒性有不同的看法和见解，这样的讨论很好，杨博当时就问我，能不能就一个专题展开讨论，让大家找来不同的文献加以论证？我自己认为这样可能更有助于让大家充分参与，提高大家的积极性！只是需要大家自己去找文献！下面这一篇文献我以前读过的，很有代表性和权威性，大家不妨读一读！
RESEARCHERS REVERSE DOPAMINERGIC NEURON LOSS IN PARKINSON
MODELS
[ORIGINAL
ARTICLE] Samson,
Kurt
ARTICLE IN BRIEF
[check mark] By introducing a gene that
manufactures an excess of a special cellular transfer protein,
investigators countered alpha-synuclein's toxic gridlock and
restored norm
al traffic to dopamine-producing neurons, according to a new
study.
Working with rudimentary
animal models of Parkinson disease (PD), a multicenter team of
researchers found a way to protect and rescue neurons from
degeneration and death. They did so by genetically bolstering
proteins involved in a key transport mechanism between cells that
fails due to the rogue activity of another protein's genetic
mutation.
If replicated in human studies, the research
could lead to new therapeutic approaches to PD, according to
authors of the study published in the July 21 Science (2006;313:
24–328).
The researchers discovered that a genetic
defect in PD causes a surplus of the protein alpha-synuclein to
accumulate in nerve cells, blocking the internal traffic of
proteins necessary for normal cellular activity in the substantia
nigra. By introducing a gene that manufactures an excess of a
special cellular transfer protein, they countered alpha-synuclein's
toxic gridlock and restored normal traffic to dopamine-producing
neurons.
“For the first time we were able to repair
dopaminergic neuron loss, the specific cells that are damaged in
Parkinson disease,” said study co-author Aaron Gitler, PhD, a
Post-doctoral Fellow at the Whitehead Institute for Biomedical
Research at the Massachusetts Institute of Technology in Cambridge,
MA.
Researchers have long associated the
presence of Lewy bodies with the loss of dopamine-producing neurons
in the substantia nigra. Exactly how Lewy bodies contributed to the
pathogenesis of the disease has been a puzzle,
however.
LEWY BODIES: TOXIC OR
PROTECTIVE?
“It's controversial right now whether Lewy
bodies are toxic or protective. For example, forming clumps of
toxic proteins might be a good defense mechanism to sequester a
toxic protein away from the rest of the cell,” Dr. Gitler told
Neurology
Today in a telephone interview. But, he added that
mutations in the gene that encodes for the alpha-synuclein protein
have been identified in families with early-onset PD, and some of
these may increase the propensity to aggregate.
“Alpha-synuclein is the most abundant
protein in Lewy bodies, but no one knew its function,” noted Dr.
Gitler, who works in the laboratory of lead author Susan L.
Lindquist, PhD, a Whitehead and Howard Hughes Medical Institute
researcher and Professor of Biology at MIT.
“Our approach was simple. If all cells have
to deal with aggregating proteins, the mechanisms employed to deal
with them are likely highly conserved, and using simple model
systems may allow us to uncover novel mechanisms to circumvent the
toxic effects of these accumulations,” he explained.
THE YEAST FACTORY
Three years ago, the team first engineered
yeast cells that manufactured human alpha-synuclein. They
discovered that cells that made too much of the protein quickly
withered and died. Excess alpha-synuclein, they observed,
interfered with the shuttling of packets of proteins between the
endoplasmic reticulum (ER), which produces proteins in cells, and
the Golgi apparatus, which sorts, modifies, and directs them as
needed.
They reasoned that if alpha-synuclein
mutations impede this shuttling activity, genetically reinforcing
ER-Golgi transport proteins might counter this
interference.
The investigators identified 34 yeast
strains that overexpressed Ypt1p, a protein involved in ER-Golgi
trafficking. By genetically increasing expression of Ypt1p in yeast
models of the disease, the team found they could suppress
alpha-synuclein's interference in cellular transport and prevent
cell degradation and death. They then discovered that the same
process could be used in fruit flies, C. elegans, and in rat brain
cells.
“We tried this a number of different ways,
from creating transgenic animals that naturally overexpressed this
protein, to injecting a copy of the gene for this transport protein
into the neurons through a gene-therapy technique. In all cases the
results were the same: cell death ceased, and the neurons were
restored to normal health,” Dr. Gitler explained.
The researchers next genetically enhanced
the activity of Ypt1ps mammalian counterpart, called Rab1, and
found boosting Rab1 expression likewise countered alpha-synuclein
toxicity in cultured rat neurons. Toxicity was determined by
measuring the number of dopamine-producing neurons and by observing
the physical status of cells.
The researchers are continuing to work their
way up the evolutionary ladder, exploring whether other transport
genes identified in the yeast factory can provide similar
neuroprotective effects in Parkinson models.
THERAPEUTIC POSSIBILITIES
Instead of trying to protect
dopamine-producing neurons themselves, current treatments for
Parkinson disease try to restore dopamine levels in the brain or to
treat symptoms of the disease. While the team's findings may offer
new therapeutic possibilities, Dr. Gitler cautioned that the
research is far from being applicable to PD in humans.
“I need to stress that we are in the real
early days of this research. It's intriguing, but there are a lot
of details that still need to be worked out.”
While the technique significantly suppressed
toxicity in almost all cases, none saw complete suppression, he
pointed out. “This confirms our yeast studies showing that other
pathways are [also] affected by alpha-synuclein accumulation,” Dr.
Gitler said. “In humans there are probably other pathways involved,
given how many genes we found that modified alpha-synuclein
toxicity, and also other proteins.”
The team has also screened some 150,000
chemical compounds and identified several that appear to reverse
alpha-synuclein toxicity, findings the researchers plan to publish
soon, Dr. Gitler told Neurology Today.
EXPERTS COMMENT
If the research is corroborated in further
studies, the researchers may have identified the earliest point at
which alpha-synuclein begins to affect the dopaminergic process on
neurons, Ted Dawson, MD, PhD, told Neurology Today in a telephone
interview. If so, it would make an ideal target for new therapeutic
approaches, he said. Dr. Dawson is the Leonard and Madlyn Abramson
Professor of Neurodegenerative Diseases at the Johns Hopkins
University School of Medicine's Institute for Cell Engineering, in
Baltimore, MD.
“This is a really interesting study,” Dr.
Dawson continued. “Although there are always problems applying
findings in worms and fruit flies to higher species, there's a
distinct possibility that the findings can be replicated in living
animals and humans. The fact that rat neurons in culture responded
is encouraging. As things go, it appears very
promising.”
If genetic misfolding causes
alpha-synuclein's action on the ER-Golgi transport mechanism, it
suggests a potential target for gene therapy. However, if chemical
compounds can be used to counter the defect, their therapeutic
potential would be even greater, Dr. Dawson said.
He noted that other research is also
yielding important insights into alpha-synuclein activity in the
dopamine transport process, as well as other avenues that might one
day be used to prevent or arrest dopaminergic neuron
loss.
“We shouldn't discount all the other
research looking for ways to prevent alpha-synuclein, but this is
the first paper up the pike in that direction. The primary
importance is that they may have identified the earliest defect,”
he said.
“I find it most compelling that if [the
team] is correct in yeast and these other models, and if the
ER-Golgi is truly the first step in the process, then we should
focus on that for therapeutic intervention. But the question
remains whether or not there are other pathways or anything further
upstream.”
