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					Gene Function
(1) (1) SNCA gene produces α-synuclein protein
(2) It is suspected that the abnormal gene is responsible for a
significant portion of familial Parkinson's disease with onset generally
before age 60.
(3) α-synuclein has a role in neurotransmission or synaptic
organization, a small fraction of α-synuclein may be associated with
vesicular membranes but most α-synuclein is cytosolic.
(4) A single peptide of the alpha synuclein protein has been
characterized as a major component of amyloid plaque formations in
the brain (SWISS-PROT). It is involved in many neurodegenerative
disorders, e.g. Parkinson’s disease.
(5) α-synuclein may be involved in neuronal plasticity.
(6) α- and β-synucleins are selective inhibitors of mammalian
phospholipase D2 and hence may play a role in the control of synaptic
vesicle cycling.
(7) The mutation in the synuclein protein causes the synuclein protein
to aggregate, thus attracting other proteins to form a deposit that
damages
the neurons in the substantia nigra (a small area of the mid brain). This
causes a reduction in dopamine.
(8) Dopamine is a chemical substance that enables people to move
normally and smoothly and transmits signals between the substantia
nigra and another part of the brain, the corpus striatum.
(9) These signals cause your muscles to make smooth, controlled
movements.
(10) The result of this imbalance is a lack of coordination of your
movement.
(11) The classic signs of Parkinson's disease: Rigidity (Rigid muscles),
Tremor, Bradykinesia (Slowed motion)/ Loss of Movement (akinesia),
Poor balance, Walking problems. And when more serious, it produces
secondary symptoms, such as depression, sleep disturbances, dizziness,
stooped posture, constipation, dementia, and problems with speech,
breathing, swallowing, and sexual function.
Gene Structure
This picture shows human chromosome 4. The approximate
location of the alpha-synuclein gene (SNCA) on chromosome 4 is
denoted by the bracket.
SNCA, a gene codes for alpha-synuclein, is located in region three of chromosome 4 between
83,362K and 85,151K bp
Through PCR-based analysis of human and rodent cells, the SNCA gene was mapped to a
cytogenetic band 4q21 .3-q22 by fluorescence in situ hybridization (FISH).
The alpha-synuclein gene has 1549 base pairs (471 adenines, 488 thymines, 248 cytosines, and 342
guanines) within the mRNA complete sequence.
Synucleins are small proteins having 123-143 amino acids and mass 14460Da.
characterized by repetitive imperfect repeats (KTKEGV) distributed throughout most of the amino-
terminal half of the polypeptide and an acidic carboxyl-terminal region
a simple upstream repeat is required for normal expression of SNCA.
SNCA gene contains 6 exons (protein – coding region) ranging from 42 to 1110 bpBesides
exons, the SNCA gene also contains intron and promoter.


The two mutant peptides coded by SNCA found in patients suffering from Parkinson's
Disease are A53T and A30P. The A53T mutation is located in a 9 amino acid section
that connects the fourth and fifth imperfect repeats of seven in an 11 amino acid
sequence. A point mutation of guanine to adenine in nucleotide at position 209 of
SNCA gene result in the conversion of alanine to threonine.
The A30P mutation is due to the transformation of guanine to cytosine at position 88.
SNCA (a gene codes for
alpha-synuclein)
Location                 Long arm of chromosome 4
                         4q21.3-q22
Orientation              Minus strand
No. of base pair         1549 (471 A, 488T, 248 C and
                         342 G)
Exon                     Yes (6)
Intron                   Yes
Promoter                 Yes
Mutation leading to PD   A53T (due to G to A transition )
                         A30P (due to G to C transition)
Special Information
Drugs Therapy—The most commonly prescribed
medication is L-dopa (levodopa) which helps replenish
some of the lost dopamine in the brain.Sinemet, a
combination of levodopa and carbidopa, is the drug
most doctors use to treat Parkinson's disease. Recent
clinical studies have suggested that the class of drugs
called "dopamine agonist" should be used prior to
levodopa (Sinemet) except in patients with cognitive
problems or hallucinations.
Side effects of medications can also be a problem. For
some medications the side effects are most severe when
the person first begins taking the drug and gradually
disappear or lessen. For other medications, side effects
may appear after several years. For example, long-term
levodopa use may result in large uncontrollable
movements (nodding, twitching or jerking) called
"dyskinesias," or "on-off" attacks where the person will
become frozen (can't move) for a few seconds or
minutes. Confusion may develop as a side effect after
about eight years.
Surgery –This is used when symptoms become very
disabling and are not responding to drug therapy.
Additionally, people that undergo surgery must be in good
health overall, younger than 70, and mentally competent
(no cognitive symptoms or dementia). There are three
types of surgery for PD: lesioning (ablative), deep brain
stimulation (DBS), and restorative (transplants).
In lesioning surgery, a very small part of the brain is
destroyed. Deep brain stimulation involves the
implantation of a small wire in the brain through which
high frequency stimulation can be sent by the person to
control his or her symptoms. In restorative surgery, new
nerve cells are implanted in the brain to take the place of
the nerve cells that have died.
Thalamotomy: Lesioning surgery in which a small portion of the
thalamus is destroyed.
Improves: Tremor.
Somewhat Improves: Rigidity (stiffness).
Does not Improve: Bradykinesia.
Pallidotomy: Lesioning surgery in which a portion of the globus pallidus
is destroyed. Long-term studies indicate that the improvements may last
for five years or longer.
Improves: Dyskinesia, Rigidity, Tremor.
Somewhat Improves: Balance, Freezing, Walking, Soft speech.
STN DBS: Deep brain stimulation of the subthalamus nucleus. May be
the most promising surgery. Not approved by FDA.
Improves: Slowness, Rigidity, Tremor, Dyskinesia, "On-Off" problems,
Increases "On" time, Reduction in levodopa needed.
Thalamus DBS: Deep brain stimulation of the thalamus.
Improves: Tremor.
GPi DBS: Deep brain stimulation of the globus pallidus, pars interns.
Usually done bilaterally. Not approved by FDA.
Improves: Dyskinesia.
Somewhat Improves: More "On" time, Tremor, Slowness, Rigidity.
   Implanting pig embryonic cells into the brains
of people with Parkinson's disease may help
improve symptoms in some patients !!
    A new study with 12 Parkinson's patients showed that an
implant totaling 12 million embryonic pig cells into three
different brain areas resulted in an average 19% improvement
in symptoms through 1 year after surgery. Three of these
patients showed a 30 to 50% improvement in symptoms.
    A loss of brain cells that communicate using a chemical
called dopamine is a common physiological characteristic of
Parkinson's disease. A decrease in dopamine cells in brains
areas like the substantia nigra and basal ganglia are thought to
contribute to the potentially severe tremors and difficulty
with movement that these patients experience.
    The researchers used pig embryonic cells because they are
structurally similar to human dopamine cells. Also, pigs have
large litters, providing the large amount of tissue needed for
transplantation. In the study, the pigs were kept in a sterile
environment to prevent them from obtaining pathogens or
transmitting them to the human recipients.
Although transplantation with human fetal cell material for
Parkinson's disease has worked in some patients, it is very difficult to
get the large number of cells needed to do those studies, and also in
certain areas of the country and this state there may be problems
with moral and ethical concerns. Those may be avoided by going to
another source.
       "The bottom line is this pig tissue does work. It is an
alternative to the use of human fetal tissue," said Judy Rosner,
former executive director of the United Parkinson Foundation of
Chicago, which recently merged with the Parkinson's Disease
Foundation in New York. "I see this as a promising line of treatment."
By replacing these lost dopamine neurons with fetal cells which have a
greater ability to thrive in a new environment than adult cells do, the
researchers hypothesized that people with Parkinson's could regain
some of their lost functions. One gentleman who previously had 2 or 3
hours a day where he might have to crawl up stairs and could barely
walk now can walk easily most of the day. He stopped using his cane,
and he's able to do many more tasks with his hands. He's even
elected to, at certain times, not take his regular doses of medicine
because he's moving well.
None of the patients experienced any adverse effects due to
the surgery, and none became worse after the procedure. One
patient died of a condition unrelated to Parkinson's or the
surgery 7 months after the procedure, the researchers noted.
They also reported that none of the patients became infected
with porcine endogenous retrovirus, a virus found in pigs that
has the potential to be transmitted to humans.
Another concern was that the human recipients would reject
the cells of another species. Half of the patients received
immunosuppressant drugs to prevent rejection, and half the
patients received cells that had been pretreated with an
antibody that lowered the chances of rejection. Treating the
cells with this antibody eliminated the need for
immunosuppressant drugs. Both groups of patients did just as
well after the procedure.
References:
www.bio.davidson.edu/courses/genomics/2001/madden/assignment1.html
web.txwes.edu/biology/macclark/genetics/genepages/david/GenePaperFinal.htm
http://www.ncbi.nlm.nih.gov/disease/Parkinson.html
http://bioinfo.cnio.es/cgi-bin/db/genecards/carddisp?SNCA
http://www.ebi.ac.uk/proteome/HUMAN/chromosomes/disease_set/4.html
http://iubio.bio.indiana.edu:8089/.bin/fbidq.html?HUgn6622
http://www.hosppract.com/genetics/0002mmc.htm
http://www.uphs.upenn.edu/cndr/research1/tausyn/tausyn.htm
http://www.neurologychannel.com/parkinsonsdisease/symptoms.shtml
http://westwood.fortunecity.com/farhi/756/
http://www.neurologychannel.com/parkinsonsdisease/index.shtml#cause
http://www.caregiver.org/factsheets/parkinsons.html
General Introduction by Wu Hang Lam
Gene Function by Chow Pui Ling
Gene Structure by Chow Hiu Kwan
Special Information by Leung Ka Ki