Determining exactly how many individuals there are in the world that are affected by Parkinson’s is a difficult task. Previously, a lot of ‘gues-stimation’ has been used in these quantitative efforts. But a clearer idea of the geographical, national and regional spread of Parkinson’s burden, could provide us with very useful information to help better understand the condition.
The Global Burden Disease Collaborators conducted a world-wide assessment of Parkinson’s burden in 2016, and this week the results of their study were published. The findings make for interesting reading.
In today’s post, we will review the results and discuss what they mean for the Parkinson’s community.
This is one of those classic ‘boy meets girl’ stories… but with a ‘saves the world’-kind of twist to it.
Having just graduated from Duke University (with a degree in computer science and economics) in the summer of 1986, Melinda Ann French began working as an intern for IBM. Having learnt to program (in Basic) on Apple II computers during her teens, she was interested in a future career in the developing world of computer technology.
She eventually scored a job with a new company called Microsoft, and for the next 6 years she climbed the corporate ladder, from a software marketing position to general manager of information products (such as Microsoft Bob, Expedia, and Encarta).
Melinda met William (Bill) Henry Gates III four months after starting her job at Microsoft – they happened to sit next to each other at a trade-fair dinner in New York. But several months would pass by before Bill actually asked her out on a date.
They were married in Hawaii on New Years day 1994.
In 2000, the couple launched the Bill and Melinda Gates Foundation – which has gone on to become one of the largest private foundations in the world with US$50+ billion in assets.
Excuse me, this is all very interesting, but what does it have to do with Parkinson’s?
It is very closely associated with Parkinson’s disease, given that people with genetic mutations in the alpha synuclein gene are more vulnerable to the condition, AND the protein is a key component in the disease-related circular aggregations (called ‘Lewy bodies’) in the brain. Recently researchers have identified proteins that may be involved with the transfer of Alpha Synuclein between cells – the method by which the disease is believed to be spreading. By blocking or removing these proteins, the researchers have been able to block the transfer of alpha synuclein.
In this post, we will review the research and discuss what this could mean for Parkinson’s disease.
Science conference. Source: JPL
At the recent annual Society for Neuroscience conference in sunny San Diego, Dr Ravindran Kumaran, a neuroscientist in the laboratory of Professor Mark Cookson (at the National Institute on Aging in Bethesda, Maryland) stood up and presented data about an interesting protein that few people in the audience had ever heard of.
Title: High-content siRNA screen identifies cellular modifiers of pre-formed alpha-synuclein fibril uptake
Authors: Kumarani R, Fernandez D, Werner-Allen JW, Buehler E, Bax A, Lai-Nag M, Cookson MR.
Source: Click here to see the full abstract
Dr Kumaran and his colleagues had systematically removed the function of each gene – one by one – in cell cultures of human cancer cells, and then measured the efficiency of the cells to absorb (or ‘take up’) the Parkinson’s related protein, alpha synuclein. An absolutely laborious task (remember there are over 20,000+ genes), but when they turned off a gene called TM9SF2, something amazing happened:
The cells absorbed 75% less of the free floating alpha synuclein than normal health cells.
This caused a bit of excitement in the Parkinson’s research community. Here was a potential method of blocking the spreading of alpha synuclein.
The funny thing is: few people had ever heard of TM9SF2, and yet Dr Kumaran then showed that TM9SF2 is in the top 3% of all proteins present in the brain. In fact, the highest concentrations of TM9SF2 are in the substantia nigra and other brain regions that are most affected by Parkinson’s disease.
So you can hopefully understand why some people in the Parkinson’s research community thought that this was a wee bit exciting.
Plus, this data presentation came on the back of another study that was published in September which presented another protein (called Lag3) that exhibited a similar ability to reduce the absorption of alpha synuclein:
Title: Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3.
Authors: Mao X, Ou MT, Karuppagounder SS, Kam TI, Yin X, Xiong Y, Ge P, Umanah GE, Brahmachari S, Shin JH, Kang HC, Zhang J, Xu J, Chen R, Park H, Andrabi SA, Kang SU, Gonçalves RA, Liang Y, Zhang S, Qi C, Lam S, Keiler JA, Tyson J, Kim D, Panicker N, Yun SP, Workman CJ, Vignali DA, Dawson VL, Ko HS, Dawson TM.
Journal: Science. 2016 Sep 30;353(6307).
In this study, the researchers conducted a screen of 352 proteins that sit on the membrane of cells. They were measuring the level of alpha synuclein binding. They identified three interesting candidates for further investigation, include lymphocyte-activation gene 3 (LAG3), neurexin 1β, and amyloid β precursor-like protein 1 (APLP1).
When the researchers compared the three, they found that by removing LAG3 less alpha synuclein was taken into the cell (by endocytosis) than the other two proteins. In addition, when they increased the amount of LAG3 that a cell produces, they observed a similar increase in the amount of alpha synuclein absorbed by cells.
Next the researchers investigated the transmission of alpha synuclein between brain cells in both normal cells and cells that had no LAG3, and they found not only that LAG3 is required for the transmission, but the absence of LAG3 reduces the damage caused by the transmission.
Finally the researchers used small proteins (antibodies) to bind to and block LAG3, and they observed less transmission and damage caused by alpha synuclein. In their conclusions, the authors pointed out that LAG3 is not the only protein involved with the transmission of alpha synclein – there will be others – but it represents a potential future target for therapeutic intervention in Parkinson’s disease.
So what does this mean?
If the theory of alpha synuclein – that this protein is passed between cells, causing the spread of the disease – is correct, then any agent that can block that transmission should slow down or halt Parkinson’s disease. We have previously talked about vacines and antibodies against alpha synuclein being tested in the clinic (Click here, here and here for more on this), but blocking TM9SF2 and LAG3 represent a new method of preventing the transmission of alpha synuclein. This is very exciting. The more angles of attack that we have for designing a treatment the better our options.
Schematic of how LAG3 may be working. Source: Science
We will be watching the field very closely and will keep you posted as new information comes to hand.
The banner for today’s post is sourced from Keepcalm-o-matic