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New variant of Parkinson’s protein goes against the grain

Short α-synuclein peptide affects uptake of dopamine rather than forming typical clumps in the brain

by Celia Henry Arnaud
July 19, 2018 | A version of this story appeared in Volume 96, Issue 30


A newly identified truncated form of the protein α-synuclein, which is best known for forming clumps in the brains of people with Parkinson’s disease, appears not to form clumps as usual.

A scheme showing two neurons, one releasing dopamine and taking it back up through a dopamine transporter and the other taking up dopamine through a dopamine receptor.
Credit: ACS Chem. Neurosci.
41-syn, a truncated form of α-synuclein, plays a role in dopamine balance by enhancing the reuptake of dopamine through dopamine transporters.

A team led by Shasi V. Kalivendi of the Indian Institute of Chemical Technology found the new variant, which is the shortest one yet, in autopsied brain tissue taken from people known to have Parkinson’s (ACS Chem. Neurosci. 2018, DOI: 10.1021/acschemneuro.8b00140). Shortened versions of the protein result from alternative splicing that excludes part of the gene transcript from being translated into protein. The new variant lacks two of α-synuclein’s normal regions. The transcript includes a premature stop codon, which produces a 41-amino acid peptide (41-syn) instead of the expected 78-amino acid protein.

Unlike other forms of α-synuclein, 41-syn plays no role in fibril formation. It doesn’t aggregate itself and neither enhances nor inhibits the aggregation of other forms of α-synuclein. In addition, it doesn’t harm isolated dopamine-producing cells.

But it does appear to play a role in dopamine balance. Cells treated with 41-syn take up more dopamine than ones not exposed to the peptide. The effect depended on both the dose and exposure time. The researchers could block this effect by inhibiting the dopamine transporter.

The new variant is unexpected and must be further characterized, says Katrin Beyer, who specializes in genomics of synuclein-related diseases at German Trias i Pujol Research Institute. “The property of 41-syn enhancing dopamine uptake should be further explored, since it could be useful for the future development of a treatment.”


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