New research – the disorder of Alpha Synuclein

A couple of interesting scientific papers were published this week dealing with the Parkinson’s disease-related protein, Alpha Synuclein. If you are not familiar with it, we suggest that you check out our primer page on Alpha Synuclein before reading any further.

So, what’s new in the world of Alpha Synuclein?

Two studies.

One in the prestigious journal Nature and the other in her sister Nature Communications. Both studies came from the same lab (good job guys!)

The first study :

Theillet-title

Title: Structural disorder of monomeric α-synuclein persists in mammalian cells.
Authors: Theillet FX, Binolfi A, Bekei B, Martorana A, Rose HM, Stuiver M, Verzini S, Lorenz D, van Rossum M, Goldfarb D, Selenko P.
Journal: Nature. 2016 Jan 25.
PMID: 26808899

This first study presented a very detailed analysis of the structure of alpha synuclein – at the atomic level – inside living cells.

Interestingly, when the researchers injected alpha synuclein (at concentrations that have been observed in normal neurons) into 5 different types of cells (both neuron and others types), they found that the protein remains extremely disordered – it changed shape rapidly. They determined this by using nuclear magnetic resonance spectroscopy (try saying that 3 times really fast!), which provides a shallow peak readout for stable proteins and a sharp peak for disordered proteins (see image below).

nature16871-f1

The researchers found a lot of sharp peaks in cells that they injected Alpha Synuclein into. Source: Nature

Rather remarkably, despite the fact that disordered proteins are usually removed from cells by enzymatic degradation, the alpha synuclein that was injected by these researchers appears to have remained intact in the cells for several days (50+ hours). And the cells did not seem to be adversely affected by this.

The second Alpha Synuclein study published this week illustrated an equally interesting result:

Binolfi-title

Title: Intracellular repair of oxidation-damaged α-synuclein fails to target C-terminal modification sites.
Authors: Binolfi A, Limatola A, Verzini S, Kosten J, Theillet FX, May Rose H, Bekei B, Stuiver M, van Rossum M, Selenko P.
Journal: Nature Communications, 2016 Jan 25;7:10251.
PMID: 26807843

In this study, the researchers injected damaged alpha synuclein into cells and then watched the cells try to repair that damaged protein. There are specific enzymes that help to maintain/repair proteins like Alpha Synuclein inside each cell. This is a normal recycling process for cells, but something interesting happened with this damaged version of alpha synuclein: only one end of the protein was repaired. The other end (called the C-terminus) was left damaged and this end failed to function correctly.

fnins-09-00059-g001

The structure of Alpha Synuclein. The c-terminus is the area in red. Source: Frontiers in Neuroscience

This led the authors to conclude that damage can cause the accumulation of chemically and functionally altered Alpha Synuclein in cells.

What does this mean for Parkinson’s disease?

The results are very interesting and the researchers should be congratulated on the complexity of their work. The findings add to our understanding of Alpha Synuclein, but both of these results need to be replicated and expanded on before we can fully appreciate their impact.

One possible implications of the results is that designing drugs to target Alpha Synuclein may be more complicated than originally thought. If the protein remains as disordered as the first study suggests, it could be difficult to target. Further investigations, however, focused on the c-terminus end of Alpha synuclein may offer novel targets for therapies looking to clear damaged proteins from cells.

If Alpha Synuclein is the big, bad enemy in Parkinson’s disease, we now know a lot more about him and we can focus on his weaknesses.

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