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Dr. Helix and Mr. Sheet
The two faces of α-synuclein
Wauwatosa East High School SMART Team: David Covell, Nate Deisinger, Neha Hasan, Brian Hoettels,
Kelly Hubert, Elyssa Kenagy, Nate Kolpin, Matt Marti, Lucia Roegner
Advisor: Mary Anne Haasch
Mentor :Jason Kowalski, Medical College of Wisconsin
α-synuclein, a benign protein involved in neurotransmitter regulation, is also
associated with neurodegenerative diseases, including Parkinson’s Disease (PD)
and Lewy Body Dementia (LBD). PD affects 500,000 people every year, and is
linked to the degeneration of motion control centers in the brain. LBD is a disorder
that affects cognitive, autonomic, and sleeping habits in people over 65. α-synuclein
helps regulate synaptic vesicle pools, dopamine, and the formation of soluble Nethylmaleimide-sensitive factor (SNARE) complexes which help vesicles fuse with
the membrane, as well as other less-studied functions. α-synuclein’s most
understood function is the regulation of vesicle pools in neurons. When no αsynuclein is present, vesicles ‘dock’ with a membrane, fusing and releasing
neurotransmitters which transmit signals in the brain. When α-synuclein
accumulates, the vesicles are prevented from fusing and releasing
neurotransmitters. Depending on the environment α-synuclein can take the shape
of an α-helix, β-sheet, or be unstructured. For instance, α-synuclein is unstructured
until it nears a membrane, where it takes on an α-helical conformation: an
advantage in fusing with the membrane. The β-sheet conformation is found primarily
in Lewy Bodies in PD and LBD patients. In order to understand α-synuclein’s role in
PD and LBD, scientists must first learn more about its structure and function;
research being carried out even today.
Glu to Lys
Ala to Thr
Ala to Phe
Amino acid mutations in
Familial Parkinson’s
Binding
Point of vesicle binding that forms
α-helix when in proximity to
membrane
NAC
Unstructured
NAC region found as beta
sheets in Lewy Body plaques.
Dr. Helix
α-synuclein: Helical Form (normal)
Figure 1
Source: http://www.about-dementia.com/articles/aboutparkinsons/parkinsons-causes.php
1XQ8.pdb
The red amino acids are hydrophilic,
and the blue hydrophobic. When αsynuclein takes its helical form, it
causes the hydrophobic amino acids
to line up on one side of the
molecule. This allows it to bind to
the membranes.
J Neurosci, 2007. 27(10): p. 2433-4
Neurons communicate with one another via chemical signals or
neurotransmitters; an example of which is dopamine. Dopamine is a
hormone associated with motor activity, sleep, mood, cognition and
behavior. The process of neurotransmitter release is illustrated above.
Vesicles containing neurotransmitters dock and fuse with the plasma
membrane, releasing neurotransmitters. α-synuclein regulates this process
by slowing the release of dopamine.
Mr. Sheet
Parkinson’s Disease
β-Sheet Model (abnormal)
Lewy Body Dementia
•Group of conditions called motor
system disorders.
•Involves dementia and motor symptoms.
•Symptoms include trembling,
stiffness, impaired balance and
slowness of movement.
•Dementia caused by damage in the brain.
•Similar to Alzheimer’s disease.
•Symptoms include hallucinations, memoryrelated problems, motor problems, trouble with
speech.
•Chronic and progressive.
•1 in 200 will get Parkinson’s Disease
during their lifetime with the risk
increasing with age.
http://health.allrefer.com/health/parkinsons-diseasesubstantia-nigra-and-parkinsons-disease.html
•Rate doubles for people over 60.
•More common in men than women.
A model for α-synuclein β-sheets
forming fibrils. Three proteins stack to
form the fibril.
•Second most common form of dementia after
Alzheimer’s.
•20% of the 7 million cases of dementia in the
United States.
• 33% of dementia illnesses in elderly
Americans.
•No specific cause known.
www.nlm.nih.gov.medlineplus
Micrograph of brain cells. The
arrow points to a Lewy body,
the light purple sphere.
•No specific cause known.
Source: http://www.about-dementia.com/articles/aboutparkinsons/parkinsons-causes.php
J Neurosci, 2007. 27(10): p. 2433-4
Excess α-synuclein blocks the vesicles from docking on the plasma
membrane. Thus, no signal is passed between the neurons.
A SMART Team project supported by the National Institutes of Health (NIH) – National Center for Research Resources Science Education Partnership Award (NCRR-SEPA)