Parkinson’s disease (PD) is a degenerative neurological disease characterized by tremor, slowness, and gait and balance difficulties that affects approximately 1 million people in the United States. The symptoms are caused by degeneration and loss of neurons in the brain, particularly those crucial for the initiation and coordination of movement. Current treatments for PD can reduce symptoms, however, they do not slow the inevitable worsening of the disease. To slow or halt illness progression, the global medical community must first determine why and how the neurons are dying. Now, a study from researchers at the University of Pittsburgh identifies the reason why the Parkinson’s-related protein alpha-synuclein, a major constituent of the Lewy bodies that are the pathological hallmark of PD, is toxic to neurons in the brain. The team state that their findings have the potential to lead to new therapies that could slow or stop progression of the devastating illness.
Previous studies show that in general 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. Past studies 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. The current study uses a well-established rodent model of PD to show exactly how alpha-synuclein disrupts mitochondrial function.
The current study shows that when alpha-synuclein attaches to the mitochondrial protein called TOM20, it prevents the mitochondria from functioning optimally, which results in the production of less energy and more damaging cellular waste. Results show that this binding prevented the interaction of TOM20 with its co-receptor, TOM22, and impaired mitochondrial protein import. Data findings show that consequently, there were deficient mitochondrial respiration, enhanced production of reactive oxygen species, and loss of mitochondrial membrane potential.
Examination of postmortem brain tissue from PD patients reveals an α-synuclein–TOM20 interaction in dopaminergic neurons associated with the loss of imported mitochondrial proteins, thereby confirming this pathogenic process in the human disease.
The researchers state that, using cell cultures, they also found two ways to prevent the toxicity caused by alpha-synuclein, a 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, preventing alpha-synuclein’s harmful effects on mitochondria.
The team surmise that their study has identified a mechanism the global medical community can target to create new treatments for this devastating disease. For the future, the researchers state that while more research is needed to determine whether their approaches can help PD patients, they are 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.
Michelle Petersen is the founder of Healthinnovations, having worked in the health and science industry for over 21 years, which includes tenure within the NHS and Oxford University. Healthinnovations is a publication that has reported on, influenced, and researched current and future innovations in health for the past decade.
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An avid campaigner in the fight against child sex abuse and trafficking, Michelle is a passionate humanist striving for a better quality of life for all humans by helping to provide traction for new technologies and techniques within healthcare.