June 5, 2017
An illustration of the alpha-synuclein protein. Credit: RCSB Protein Data Bank
Parkinson's
disease is a debilitating neurological illness that affects approximately 10
million people worldwide. It is marked by a progressive decline in physical
function, the most iconic being uncontrollable tremors, and involves the
malfunction and eventual death of nerve cells located in the brain. There is no
cure for this disease, and researchers have struggled for years to fully
understand its cause. In the 1990s, the field of Parkinson's research took a
great leap forward when an overabundance of the protein alpha-synuclein was
linked to disease development. This protein, a mysterious inhabitant of the
brain, is found mainly at the end of neurons in what is called the nerve
terminal. Attempts to precisely identify its role in Parkinson's since the link
was discovered have been unsuccessful, until now.
Researchers
at the Okinawa Institute of Science and Technology Graduate University (OIST)
have found that the protein hinders a key step involved in the transmission of
neuronal signals, which is essential for higher-brain functioning: vesicle
endocytosis at the nerve terminal. The study has been accepted for early
release in the Journal of Neuroscience.
Neurotransmission is a
process that allows neurons to pass signals between one another—signals
important for motor, sensory, and cognitive functioning. When an electrical
signal arrives at a nerve terminal and needs to be passed along to the next
neuron, neurotransmitters, or chemical messengers, packed in vesicles mediate
this process. A vesicle is a container made of a lipid membrane from which a
neurotransmitter is released into the synaptic cleft—the space between neurons.
After being released, the neurotransmitter is caught by receptors in an
adjacent neuron and the signal is passed along for further transmission.
Meanwhile, the empty vesicle is recycled back into the nerve terminal to be
used again.
The retrieval of an emptied
vesicle membrane is called "endocytosis," and it is this process that
an overabundance of alpha-synuclein disrupts. Endocytosis is critical for
proper neurotransmission—when it is inhibited, the rest of the steps involved
in transmission are affected as well.
"If you inhibit [endocytosis in the nerve terminal], then the
vesicle recycling becomes slower and the supply of the vesicles is
inhibited," OIST Professor Tomoyuki Takahashi from the Cellular and
Molecular Synaptic Function Unit explains. "If you are using the vesicles
mildly, this is okay, but if you start to use them heavily, then it
becomes a problem."
The vesicles are represented by blue and white circles at the top left. The white circles are empty and the blue ones contain a neurotransmitter. "Full" vesicles move toward the membrane of the nerve terminal, represented by the overall outline of the figure, where they attach and fuse into the terminal membrane, thereby releasing the transmitter into the space between neurons, the synaptic cleft. This release is illustrated by a blue omega-shaped structure at the bottom of the terminal membrane. When a vesicle becomes "empty," the vesicle membrane is retrieved into the terminal -- white circles on the right -- and then recycled back to the release sites, which are illustrated as red bars. Credit: Okinawa Institute of Science and Technology Graduate University (OIST)
High-frequency
transmission, in which vesicles are heavily used, is important for processes
such as sensory perception, generating memories, and motor control. The OIST
researchers found that when endocytosis is inhibited, high-frequency
transmission breaks down much more quickly than it would under normal
circumstances.
A deeper look into the
mechanism by which alpha-synuclein inhibits endocytosis revealed toxic effects
of the over-assembly of microtubules.
"Microtubule is a
structure protein," Professor Takahashi explains. "It's like a pillar
of a house." Apparently, too much alpha-synuclein in the nerve terminal causes
microtubules to over-assemble and somehow get in the way of endocytosis. It is
like having too many pillars in a house and in all the wrong places—one could
imagine such a house would be difficult to live in and navigate properly.
Researchers believe that
this inhibitory process caused by an overabundance of alpha-synuclein is what
occurs in the early stages of Parkinson's disease, before morphological changes
such as the loss of function and death of neurons begins.
When asked whether these
results can help aid in developing treatment for Parkinson's disease, Professor
Takahashi replies: "I think we are getting close. We know the initial
target and the mechanism...[But] in order to step into [the treatment] stage,
we should probably work a little bit more to know by what mechanism the
microtubules interfere with endocytosis."
More information: Kohgaku
Eguchi et al, Wild-type monomeric α-synuclein can impair vesicle endocytosis
and synaptic fidelity via tubulin polymerization at the calyx of Held, The Journal of Neuroscience (2017). DOI: 10.1523/JNEUROSCI.0179-17.2017
https://medicalxpress.com/news/2017-06-mechanism-parkinson-disease-revealed.html
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