By Danielle Bradshaw from In The Cloud Copy

A research team has found a connection that ties disease-linked alpha-synuclein proteins and their tendency to loosely combine (or to aggregate) and misfold (which essentially means that they form into an improper shape). The team’s research – that they published in Nature Communications – expresses that there are new ways in which therapy for Parkinson’s can be administered.

What is Alpha-synuclein and Parkinson’s Disease?

Alpha-synuclein or aSyn proteins can be found inside of the brain; more specifically at the very ends of neurons which themselves can be found inside of presynaptic terminals. Aggregated alpha-synuclein proteins are a key feature in neurodegenerative illnesses in which the central nervous system’s cells gradually stop functioning and die – such as with Parkinson’s.

With Parkinson’s disease, aSyn becomes unstable and improperly formed after which it combines into fibrils (think of biological fibers that form structures within the body) that are immune to degradation. These “insoluble fibrils” are a trademark of the disease. The major issue with this knowledge, however, is that it doesn’t answer the question of why aSyn misfolds in the first place. Without that answer, there’s no way to actually cure Parkinson’s.

A Quest for Answers

Dr. Amberley Stephens, a co-author of the University of Cambridge Department of Chemical Engineering and Biotechnology’s research papers on the matter, said that the team wanted to figure out why healthy and fully functional aSyn protein starts to misfold. Dr. Stephens says that having a better understanding of the first steps of how the protein begins to unfold can possibly lead to new means by which illnesses caused by this problem can be treated.

The Study Commences

The issue with this, though, is that aSyn doesn’t really exist as a singular, unified structure but rather as multiple, transitional ones that change often. To find a way to make aSyn stop gathering together inside of neurons, the team had to figure out what shape aSyn monomers make when it is forming aggregations as opposed to when it isn’t (which in turn means that it stays in its monomeric form).

To this end, the team added the ion calcium, to make the aSyn group together more rapidly. In order to actually observe the small discrepancies in the monomeric protein’s structure, they used a plethora of advanced investigative practices so that they could see the various changes within the aSyn down to the molecular level. It was hoped that this would enable them to see whether or not the aSyn was in an aggregated or non-aggregated state.

All Eyes on aSyn

But how did they observe aSyn exactly? Maria Zacharopoulou (the first co-author of the University of Cambridge’s paper) says that they used the hydrogen-deuterium exchange mass spectrometry and this allowed them to see – and thus, better understand – the positioning of the protein.

She goes on to say that their colleagues at the University of Exeter are working on tools that can help them better spot even the most infinitesimal differences among groups of aSyn. Zacharopoulou says that being able to observe aSyn so closely is important as the protein is incredibly adjustable.

What the Study Found

The researchers discovered a particular area referred to as the N-terminus of aSyn which they discovered was located at the start of the protein sequence. They found that the N-terminus becomes more and more exposed and actually opens up once the calcium ion is introduced to induce aggregation. The team also discovered that the speed of the aSyn’s aggregation depended heavily on how exposed the N-terminus was; the less exposed proteins didn’t cluster together at all.

In the end, the team found that changes within a person’s proteins or the existence of inherited mutations that can cause Parkinson’s are what lead to the structural transformation in the monomeric aSyn protein. This discovery offered an amazing look into Parkinson’s disease – more specifically what happens at the beginning of the disease’s onset and new targets at which to focus therapeutic treatments (such as ensuring that the closed aSyn protein structures remain stable)

Next, researchers will work on separating aSyn proteins that are liable to aggregate and those that are not from monomeric proteins so that they can create therapies that keep the aSyn proteins from misfolding.

To learn more about this research, click here.