Gaucher disease is a genetic disorder caused by the reduced activity of an enzyme, glucocerebrosidase. This enzyme is produced by a region of DNA (or a gene) called GBA – the same GBA gene associated with a particular form of Parkinson’s.
Recently, a Danish company has been testing a new drug that could benefit people with Gaucher disease.
It is only natural to ask the question: Could this drug also benefit GBA-associated Parkinson’s?
In today’s post, we will discuss what Gaucher disease is, how this experimental drug works, and why it would be interesting to test it in Parkinson’s.
Will Shakespeare. Source: Ppolskieradio
The title of this post is a play on words from one of the many famous lines of William Shakespeare’s play, Hamlet.
The original line – delivered by Marcellus (a Danish army sentinel) after the ghost of the dead king appears – reads: If the authorities knew about the problems and chose not to prevent them, then clearly something is rotten in the state of Denmark.
(Act 1, Scene 4)
The title of this post, however, is: Something is interesting in the state of Denmark
This slight change was made because certain Danish authorities know about the problem and they are trying to prevent it. The ‘authorities’ in this situation are some research scientists at a biotech company in Denmark, called Orphazyme.
And the problem is Parkinson’s?
No, the problem is Gaucher disease.
Huh? What is Gaucher disease?
For many people diagnosed with Parkinson’s disease, one of the scariest prospects of the condition that they face is the possibility of developing dyskinesias.
Dyskinesias are involuntary movements that can develop after long term use of the primary treatment of Parkinson’s disease: Levodopa
In todays post I discuss one experimental strategy for dealing with this debilitating aspect of Parkinson’s disease.
Dyskinesia. Source: JAMA Neurology
There is a normal course of events with Parkinson’s disease (and yes, I am grossly generalising here).
First comes the shock of the diagnosis.
This is generally followed by the roller coaster of various emotions (including disbelief, sadness, anger, denial).
Then comes the period during which one will try to familiarise oneself with the condition (reading books, searching online, joining Facebook groups), and this usually leads to awareness of some of the realities of the condition.
One of those realities (especially for people with early onset Parkinson’s disease) are dyskinesias.
What are dyskinesias?
Dyskinesias (from Greek: dys – abnormal; and kinēsis – motion, movement) are simply a category of movement disorders that are characterised by involuntary muscle movements. And they are certainly not specific to Parkinson’s disease.
As I have suggested in the summary at the top, they are associated in Parkinson’s disease with long-term use of Levodopa (also known as Sinemet or Madopar).
Sinemet is Levodopa. Source: Drugs
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?
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 :
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.
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).
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:
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.
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.
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.