There is a a debate going on about alpha-synuclein.
The question is -- is alpha-synuclein cause or effect?
An anti-body has been developed in mice that cleans up and removes
the protein. There is also a fly model.
Some postulate, that alpha-synuclein is accumulating because
something else is going on, and is just a byproduct.
>From last CSR by J R Bruman:
> Papapetropoulos S et al;J Neur N'surg Psych 2001;70:662-665:
> A study of patients having a rare form of PD linked to mutation
> of alpha-synuclein revealed younger age at onset, much less
> incidence of tremor, and longer duration of the disease.
Stem cells are still a hope, but, there are many paths still open
to investigation. Understanding of the fundamental cause of PD
is still elusive.
Ray
................................................................
Sources: Reuters | AP | ABCNEWS.com | HealthSCOUT
Saturday June 30 6:46 AM ET
Gene Research Suggests How Parkinson's Might Arise
By Amy Norton
NEW YORK (Reuters Health) - Research into the genetic roots of inherited
forms of Parkinson's disease may have opened the door tounderstanding how
all forms of the degenerative disorder arise. An international team of
scientists has found that two proteins linked toinherited Parkinson's
interact in healthy brains--suggesting that a misstep in this interaction
may be involved in all cases of Parkinson's.
If future research bears out this concept, it may be possible to design a
drug that specifically targets the protein-gone-wrong, study co-author Dr.
Michael G. Schlossmacher of Harvard Medical School in Boston,
Massachusetts, said in an interview.
He and his colleagues report their findings in the June 28th issue of
Sciencexpress, the online edition of the journal Science.
Not long ago, researchers believed Parkinson's disease had no genetic
component. But in recent years, scientists have identified gene
Wolfmutations linked to inherited Parkinson's--rare forms of the disease
that typically strike relatively young people. Parkinson's usually affects
people older than 50, causing tremors, muscle rigidity, and balance and
coordination problems that worsen over time.
All cases of Parkinson's are marked by a loss of certain brain cells that
help control movement. All patients also have an accumulation of
a protein called alpha-synuclein in their brains, according to
Schlossmacher. In fact, scientists recently discovered that a mutation in the
gene for alpha-synuclein is responsible for one of the inherited forms of
the disease.
Mutations in another gene, called parkin, have been implicated in causing a
second inherited type of Parkinson's.
To see what role the parkin and alpha-synuclein proteins might play in
common forms of Parkinson's, Schlossmacher and his colleagues examined both
healthy brain tissue and tissue from patients with Parkinson's due to a
parkin mutation. They found that parkin and alpha-synuclein interact in
healthy brains, with parkin helping to clear alpha-synuclein from cells. In
brains affected by the inherited formof Parkinson's, however, parkin could
not do its job, causing alpha-synuclein to accumulate.
Because parkin and alpha-synuclein have a healthy working relationship in
normal brains, Schlossmacher and his colleagues hypothesizethat an
abnormality in this interaction may be at the root of Parkinson's. Even
though most patients do not have an overt mutation in
these genes, Schlossmacher explained, they may have a ``subtle abnormal
tuning'' in the interaction between the two proteins that allows
alpha-synuclein to accumulate in the brain.
If alpha-synuclein build-up is the trigger for the loss of nerve cells in
Parkinson's, it may be possible to design drugs that bring down levels of
alpha-synuclein, Schlossmacher said. However, he stressed, this scenario
remains about 10 years away.
This study, he said, is a ``first and significant step'' in understanding
how Parkinson's disease begins.
SOURCE: Sciencexpress 2001;10.1126.
........................................................
A resent report.
........................................................
J Neurosci 2001 May 1;21(9):3126-3134
Fate of Midbrain Dopaminergic Neurons Controlled by the Engrailed Genes.
Simon HH, Saueressig H, Wurst W, Goulding MD, O'Leary DD.
Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, California
92037, Max Planck Institute for Psychiatry, D-80804 Munich, Germany, and
GSF-Research Center, Institute for Mammalian Genetics, D-85758 OberschleiBheim,
Germany.
Deficiencies in neurotransmitter-specific cell groups in the midbrain
result in
prominent neural disorders, including Parkinson's disease, which is caused by
the loss of dopaminergic neurons of the substantia nigra. We have investigated
in mice the role of the engrailed homeodomain transcription factors, En-1 and
En-2, in controlling the developmental fate of midbrain dopaminergic neurons.
En-1 is highly expressed by essentially all dopaminergic neurons in the
substantia nigra and ventral tegmentum, whereas En-2 is highly expressed by a
subset of them. These neurons are generated and differentiate their dopaminergic
phenotype in En-1/En-2 double null mutants, but disappear soon thereafter. Use
of an En-1/tau-LacZ knock-in mouse as an autonomous marker for these neurons
indicates that they are lost, rather than that they change their
neurotransmitter phenotype. A single allele of En-1 on an En-2 null background
is sufficient to produce a wild type-like substantia nigra and ventral
tegmentum, whereas in contrast a single allele of En-2 on an En-1 null
background results in the survival of only a small proportion of these
dopaminergic neurons, a finding that relates to the differential expression of
En-1 and En-2. Additional findings indicate that En-1 and En-2 regulate
expression of alpha-synuclein, a gene that is genetically linked to Parkinson's
disease. These findings show that the engrailed genes are expressed by midbrain
dopaminergic neurons from their generation to adulthood but are not
required for
their specification. However, the engrailed genes control the survival of
midbrain dopaminergic neurons in a gene dose-dependent manner. Our findings also
suggest a link between engrailed and Parkinson's disease.
PMID: 11312297 [PubMed - as supplied by publisher]
........................................................
Here is an earlier report.
.......................................................
Ann N Y Acad Sci 2000;920:28-32
Genetics of Parkinson's disease.
Polymeropoulos MH.
Novartis Pharmaceuticals Corporation, Pharmacogenetics Department, 9 West
Watkins, Gaithersburg, MD 20878, USA. [log in to unmask]
Several genetic factors have been recently recognized as related to the etiology
of Parkinson's disease. Mutations in the genes coding for alpha-synuclein and
ubiquitin carboxy-terminal hydrolase have been identified in families with
autosomal dominant Parkinson's disease. Mutations in the Parkin gene are
responsible for autosomal recessive parkinsonism. These first pieces of the
molecular puzzle of Parkinson's disease offer novel insights into the
pathophysiology of the illness.
Publication Types:
Review
Review, tutorial
PMID: 11193165 [PubMed - indexed for MEDLINE]
.......................................................
Here is an environmental factor producing similar results.
.......................................................
Chronic systemic exposure reproduces features of Parkinson's disease
R Betarbet, TB Sherer, G MacKenzie, M Garcia-Osuna, AV Panov, JT
Greenamyre
Nature Neuroscience 2000;3:1301-1306
Rats chronically exposed to the pesticide rotenone develop most of the
cellular pathophysiologic features of Parkinson's disease, according to
this report. E-MOVE's initial report on this study from the Annual Meeting
of the American Association of Neurology is archived at
http://www.wemove.org/emove/article.asp?ID=194.
Twenty-five rats were infused for 7 days or more with 2-3 mg/kg/day of
rotenone, a highly specific inhibitor of mitochondrial complex I. (The
dose was below that needed to inhibit brain mitochondrial respiration
rates, ruling out ATP depletion as a cause of pathology.) Histochemical
analysis showed:
--12 of the 25 rats had brain lesions, versus no vehicle-treated rats.
--while complex I inhibition was found throughout the brain, lesions were
restricted to nigrostriatal dopaminergic pathways.
--"Lesions typically began focally in the central or dorsolateral portion
of the anterior striatum...and spread to involve most of the striatum."
--the pattern of areas that were most severely affected versus those that
were relatively spared matched the pattern seen in PD.
--Cytoplasmic inclusions were detected that contained ubiquitin and
alpha-synuclein. "Ultrastructural features included a homogenous dense
core surrounded by fibrillar elements similar to those seen in Lewy
bodies. Some of the inclusions had a more granular appearance, like those
described in alpha-synuclein transgenic mice."
--Preliminary observations of behavior showed that animals with
dopaminergic lesions had hypokinesia, unsteady movement, and hunched
posture. Seven animals had severe rigidity, and three had shaking of one
or more paws.
The authors conclude, "Our results indicate that a systemic partial defect
in complex I is enough to reproduce the behavioral, anatomical,
neurochemical, and neuropathological features of PD."
In a News and Views article accompanying the report, Benoit Giasson and
Virginia Lee note, "The question remains as to why rotenone, which
inhibits complex I throughout the brain, should preferentially target
dopaminergic neurons. The likely answer is that these neurons are
particularly sensitive to oxidative stress [known to result from
mitochondrial inhibition] because of the permanently elevated level of
free radicals generated by dopamine metabolism and auto- oxidation."
Copyright 2000 WE MOVE
Editor: Richard Robinson ([log in to unmask])
.......................................................
Ray Strand
Prairie Sky Design
-----------------( on the Edge of the Prairie Abyss )---------------
when the sky is clear
the ground is visible
49/dx PD 2 yrs/40? onset
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