Two Forms of Alpha-Synuclein; Two Forms of PARKINSON’S DISEASE

 

 

Two different laboratories of researchers, one in France and one in the U.S. have found that alpha-synuclein, while the same biologically and molecularly, can form two distinct types of forms or strains, which perhaps explains why people with PARKINSON’S DISEASE experience such different symptoms.

The French team from the Laboratoire CNRS d’Enzymologie et Biochime Structurales published their paper on October 10 in the Journal Nature Communications.  This team identified two distinct shapes for the aggregates of alpha synuclein, one is round, “spaghetti” like and the other is flat, “linguini” like.  The spaghetti shape is much more toxic, rapidly penetrating and ultimately killing the cells in the brain.  It is very resistant to cell chemistry that would normally be able to eliminate unwanted intruders, such as viruses or other destructive proteins.  Linguini forms on the other hand, are more easily controlled by the cell and become toxic to the cell much more slowly.

This team thinks that the differences in the shapes of the aggregates may be responsible for the differences in the symptoms of PARKINSON’S DISEASE between those that are primarily motor affected, such as tremor, and those that are cognitive or behavioral.  While they are continuing to refine their research and better characterize the structures of alpha-synuclein, they believe that this process could lead to a targeted therapeutic treatment specific to each strain.

In the US, a team led by Virginia Lee and John Q. Trojanowski, two esteemed researchers in PARKINSON’S DISEASE from the Perelman School of Medicine at the University of Pennsylvania,  have discovered that alpha-synuclein can take on two different forms despite having the same chemical make up and interact with other disease proteins found in Alzheimer’s, PARKINSON’S and other neurodegenerative disease.

Tau protein is a marker of Alzheimer’s and alpha-synuclein is a marker for PARKINSON’S.  Post mortem brains of people with PARKINSON’S who had symptoms of cognitive decline or dementia showed both tau and alpha-synuclein closely entwined. Brains of patients that did not have dementia also has aggregates of alpha-synuclein, but the shape of the protein was different.  This could correspond to the “spaghetti” and “linguini” models.  However, Lee and Trojanowski found that over time, this strain  could change into the more fibril type found with the dementia, but it took longer for it to become entangled with tau. They speculate that these different shapes assumed by alpha-synuclein may be responsible for the different symptoms observed in different PARKINSON’S DISEASE patients, why some patients have more motor symptoms and others are affected with more cognitive decline or dementia.

More research is needed to validate and explore these findings more clearly.  But it also could lead to more therapeutic targets for treatment.  If each strain can be clearly defined, it can be selectively targeted by antibodies designed specifically for each strain.  Lee says “What we’ve found opens up new areas for developing therapies and particularly immunotherapies for PARKINSON’S and other neurodegenerative diseases.”

 

 

 

Luc Bousset, Laura Pieri, Gemma Ruiz-Arlandis, Julia Gath, Poul Henning Jensen, + et al. Structural and functional characterization of two alpha-synuclein strains  Nature Communications 4, doi:10.1038/ncomms3575

Jing L. Guo, Dustin J. Covell, Joshua P. Daniels, Michiyo Iba, Anna Stieber, Bin Zhang, Dawn M. Riddle, Linda K. Kwong, Yan Xu, John Q. Trojanowski, Virginia M.Y. Lee  Distinct α-Synuclein Strains Differentially Promote Tau Inclusions in Neurons Cell: 3July2013; 154:1

 

Review by Marcia McCall

 

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