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Toxic Proteins May Interfere with Cell Transportation in PD

Scientists may have exposed why the protein alpha-synuclein is so harmful when it builds up in the brains of people with Parkinson’s disease. According to their report in the March 5 issue of the Proceedings of the National Academy of Sciences of the United States of America, the protein may stop the release of dopamine from neurons, leading to death of those neurons and the progression of PD. This clue may lead to better understanding of PD and potential therapies.

Previous studies suggested that loose strands of alpha-synuclein within brain cells are toxic. However, scientists were unsure how the proteins caused damage or how they were related to the loss of dopamine neurons that characterizes Parkinson’s disease.

To solve this mystery, an international research team led by Nam Ki Lee, Ph.D., of Korea and Yeon-Kyun Shin, Ph.D., of Iowa State University, studied how alpha-synuclein impacts the cells’ release of the neurotransmitter dopamine. They looked at both the type of alpha-synuclein found in Lewy bodies and a form of alpha-synuclein which is found elsewhere but still plays a role in the release of dopamine from cells.

They knew that in order to transport dopamine, cells rely on molecular machinery called SNARE. SNARE helps to transport dopamine by wrapping it in small packages and squeezing them out of the host cell. If SNARE jams, the package of dopamine never leaves the cell. Drs. Lee and Shin and colleagues wondered whether alpha-synuclein interfered with SNARE.

Results

  • The normal, single protein form of alpha-synuclein does not hinder the cells' ability to transport and release packages of dopamine. It is still unclear what its job is.
  • Clumps of alpha-synuclein hinder the normal movement of dopamine-containing packages inside of cells.
  • Clumps of alpha-synuclein blocked the normal release of dopamine.  Increasing the amount of alpha-synuclein clumps directly reduced the ability of cells to release dopamine.

What Does it Mean?

Scientists have known for years that alpha-synuclein and the clumps it forms, Lewy bodies are a pathological hallmark of PD. The question has been: is alpha-synuclein accumulation a result of neurodegeneration in PD, or is it the cause of it? If alpha-synuclein accumulation causes or enhances PD progression, how does it play a role in PD?  

Scientists have now identified one way by which too much alpha-synuclein can interfere with the dopamine neurons lost in PD, and possibly lead to the death of these cells. This research supports the theory that alpha-synuclein, specifically clumped alpha-synuclein, can cause toxic changes in dopamine cells. 

By now knowing one possible mechanism, scientists can rationally look for ways to prevent, halt, or even reverse this process. It will help them as they search to identify new compounds that will hopefully be tomorrow’s PD therapies.  

Reference: Choi BK, Choi MG, Kim JY, Yang Y, Kweon DH, Lee NK, Shin YK (2013) Large α-synuclein oligomers inhibit neuronal SNARE-mediated vesicle docking. Proceedings of the National Academy of Sciences USA: 4087-4092. DOI: 10.1073/pnas.1218424110 <http://dx.doi.org/10.1073/pnas.1218424110>

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Source Date: Mar 29 2013