Science Today reports that researchers at the University of Pittsburgh School of Medicine have uncovered a major reason why the Parkinson’s-related protein alpha-synuclein, a major constituent of the Lewy bodies that are the pathological hallmark of Parkinson’s disease (PD), is toxic to neurons in the brain. The finding has the potential to lead to new therapies that could slow or stop progression of the devastating illness. The new research appears online in Science Translational Medicine.
Degenerating neurons contain large clumps of a protein called alpha-synuclein. People whose cells make too much alpha-synuclein or make a mutated form of the protein are at high risk of developing PD because of the protein’s toxicity, researchers found. Scientists also demonstrated that the accumulation of alpha-synuclein in PD is toxic because it disrupts the normal functioning of mitochondria–the tiny powerhouses responsible for generating a cell’s energy.
In the new study, Dr. Greenamyre and his team–led by coauthors Roberto Di Maio, Ph.D., and Paul Barrett, Ph.D., both of PIND–used a well-established rodent model of PD to show exactly how alpha-synuclein disrupts mitochondrial function. They found that by attaching to a mitochondrial protein called TOM20, alpha-synuclein prevented the mitochondria from functioning optimally, which resulted in the production of less energy and more damaging cellular waste.
Using cell cultures, the research team also found two ways to prevent the toxicity caused by alpha-synuclein: gene therapy that forced the neurons to make more TOM20 protein protected them from the alpha-synuclein; and a protein that was able to prevent alpha-synuclein from sticking to TOM20 prevented alpha-synuclein’s harmful effects on mitochondria.
While more research is needed to determine whether these approaches could help PD patients, Dr. Greenamyre is optimistic that one or both may ultimately make it into human clinical trials in an effort to slow or halt the otherwise inevitable progression of PD.
R. Di Maio, P. J. Barrett, E. K. Hoffman, C. W. Barrett, A. Zharikov, A. Borah, X. Hu, J. McCoy, C. T. Chu, E. A. Burton, T. G. Hastings, J. T. Greenamyre. Alpha-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinsons disease. Science Translational Medicine, 2016; 8 (342): 342ra78 DOI: 10.1126/scitranslmed.aaf3634