Parkinson's is not a single disease

Little is known about how genetic mutations influence the severity of Parkinson’s disease. Some Parkinson’s patients have a protein mutation that can accelerate the disease, but how this happens is still a mystery. Scientists at École Polytechnique Fédérale de Lausanne (EPFL) have found that these mutations can cause Parkinson’s through multiple mechanisms in the cell. The discovery shows that Parkinson’s is not a uniform disease, and has significant implications for treating all forms of the disease. The study continues two recent publications from the same group, and is published in the Journal of Biological Chemistry.

Some Parkinson’s patients have the mutated version of a protein that normally helps brain cells communicate. The protein, called alpha-synuclein, is barely understood, which means that its mutated versions are even less clear. But although these mutations underlie only a small percentage of Parkinson’s disease cases, they can significantly accelerate the disease and even cause early-onset Parkinson’s, which begins before the age of 50.

Mutations behind Parkinson’s disease
A team led by Hilal Lashuel at EPFL has found that the mutations of alpha-synuclein that exacerbate Parkinson’s disease work through multiple biological mechanisms. Depending on the mutation, the protein becomes unable to “turn-on” properly or it even moves it from its normal location in the brain cell.

One of the main characteristics of Parkinson’s disease is the presence of protein clumps inside brain cells that regulate movement. These clumps contain a form of alpha-synuclein known as “phosphorylated”, which means that it has had a chemical group attached to it, turning it “on”. The clumps of phosphorylated alpha-synuclein end up disrupting communication between cells, and ultimately kill them. This is what causes the movement symptoms of Parkinson’s.

Different mutations, different pathways
In this study, the researchers studied three mutations of alpha-synuclein, all of which affect its phosphorylation, and have been linked to certain forms of Parkinson’s disease. The scientists used yeast, mammalian cells – including neurons – and live mice to see how these mutations affect alpha-synuclein.

All three mutations caused higher-than-normal phosphorylation of alpha-synuclein in mammalian and yeast cells, and even in brain tissue. But even more interestingly, the researchers found that one the three mutations caused the protein to change location inside the cell, and move to the cell nucleus and the endoplasmic reticulum, where the cell modifies new proteins. The fact that the three mutations cause alpha-synuclein to move to different parts of the cell, means that, the three mutations must work through different ways in the cell, but still resulting in the symptoms of Parkinson’s disease. This has important implications about treating the disease, which does not appear to be as uniform as previously thought.

In addition, the study shows a more effective way of studying Parkinson’s disease. Having determined that these three mutations increase alpha-synuclein phosphorylation, exploring them in different models (cells, animals etc) can provide new insights into the normal function of the protein itself, and the role it plays in Parkinson’s and even other diseases.

“This may provide unique opportunities to target specific pathological pathways in Parkinson’s or other neurodegenerative diseases caused by alpha-synuclein – which are collectively known as synucleinopathies,” says Hilal Lashuel.

This work represents a collaboration of EPFL’s Brain Mind Institute with the Max Planck Institute for Biophysical Chemistry, the Instituto de Medicina Molecular, the University of Lisboa, the University Medical Center Goettingen, the German Center for Neurodegenerative diseases, the University of California San Diego, and the Qatar Biomedical Research Institute.

One of the first authors of this publication, Martial MBefo Kamdem, holds an EPFL PhD Degree, finalized in the frame of the EPFL PhD Program in Neuroscience.

Reference
Mbefo M, Fares M-B, Paleologou K, Oueslati A, Yin G, Tenreiro S, Pinto M, Outeiro T, Zweckstetter M, Masliah E, Lashuel HA. The Parkinson's Disease Mutant E46K Enhances Alpha-Synuclein Phosphorylation in Mammalian Cell-Lines, in Yeast and In Vivo. J Biol Chem. 05 February 2015. DOI: 74/jbc.M114.610774

Previous related studies
Khalaf O, Fauvet B, Oueslati A, Dikiy I, Mahul-Mellier AL, Ruggeri FS, Mbefo MK, Vercruysse F, Dietler G, Lee SJ, Eliezer D, Lashuel HA. The H50Q mutation enhances α-synuclein aggregation, secretion, and toxicity. J Biol Chem. 2014 Aug 8;289(32):21856-76. DOI: 10.1074/jbc.M114.553297.

Fares MB, Ait-Bouziad N, Dikiy I, Mbefo MK, Jovičić A, Kiely A, Holton JL, Lee SJ, Gitler AD, Eliezer D, Lashuel HA. The novel Parkinson's disease linked mutation G51D attenuates in vitro aggregation and membrane binding of α-synuclein, and enhances its secretion and nuclear localization in cells. Hum Mol Genet. 2014 Sep 1;23(17):4491-509. DOI: 10.1093/hmg/ddu165.

Image: © Suraj Rajan/Wikipedia: A Lewy body in the substantia nigra