Alpha-synuclein interferes with cellular energy and transport
Alpha-synuclein, the protein that propagates Parkinson’s disease, appears to interfere with cellular energy production, which slows other important cellular processes and leads to cell aging and damage.
Why is it important?
Although it is now clear that alpha-synuclein plays a role in Parkinson’s disease, there are still many questions to be answered about how it damages brain cells. This study sheds light on some of these mechanisms and gives scientists a new target for developing therapies to slow or stop the disease.
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“For many years, failure of energy metabolism was considered a primary event in Parkinson’s. With the emergence of alpha-synuclein as a major player in the disease process, studies on the failure of energy metabolism received less attention. This paper is important because it brings these two disease mechanisms together and appears to provide insight into how they are linked.” Dr. Patrik Brundin
Increasing evidence indicates that problems with cellular powerplants, known as mitochondria, cause a cascade of problems that may contribute to Parkinson’s, including the build-up abnormal alpha-synuclein. This accumulation then further impairs the mitochondria, leading to a vicious cycle that aids in disease progress. However, it was unclear exactly how this relationship worked.
This study shows that a modified version of alpha-synuclein links up with a protein called TOM20, which is responsible for moving molecules into the mitochondria. The connection prevents TOM20 from binding to another protein required to keep transport into the mitochondria working. The result is a breakdown in cellular energy production.
The study found that by overexpressing TOM20 there were beneficial effects on mitochondrial functioning, suggesting this as a potential therapeutic target in Parkinson’s.
Related work and trials
Another recent study highlights a different mechanism which supports this idea of a vicious cycle of alpha-synuclein accumulation and impaired mitochondrial functioning aiding the progression of Parkinson’s. In a similar way to the study described above, this study shows that a modified version of alpha-synuclein binds to a protein called VAPB loosening its association to the mitochondria. This also disrupts cellular energy production and can result in damage to neurons.
Original article: Di Maio R, Barrett PJ, Hoffman EK, Barrett CW, Zharikov A, Borah A, Hu X, McCoy J, Chu CT, Burton EA, Hastings TG, Greenamyre JT. June 8, 2016. a-synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson’s disease. Sci Transl Med 8(342):342ra78.