Researchers from the University of Pittsburgh School of Medicine have gleaned new insights into the cellular biochemistry that underpins Parkinson’s disease. The team hopes that these new clues will help design effective drugs in the future.
Parkinson’s disease (PD) is a degenerative condition that affects the dopamine-producing cells in the human brain.
Affecting an estimated 1 million Americans, the primary symptoms include tremor, stiffness, instability, and impaired balance and coordination.
The condition steadily worsens over time until the individual can no longer care for themselves.
The cost of PD in America in 2010 was estimated to be in excess of
Currently, there is no cure for PD, but some symptoms can be relieved by drugs, including levodopa and carbidopa.
Because the exact processes by which PD affect the brain are not fully understood, designing effective treatment is challenging.
One marker that is always present in PD are Lewy bodies. These so-called fibrillar aggregates are a hallmark of neuronal degeneration. Lewy bodies consist of a tangle of proteins that steadily builds up within neurons, slowly preventing them from functioning correctly.
Lewy bodies are made up of a variety of proteins, but the primary constituent is alpha-synuclein. This protein is present in the healthy brain and appears to play a role in transmitting neurotransmitters (chemical messages) between neurons, particularly dopamine.
In PD (and some other forms of dementia) alpha-synuclein builds up to create insoluble Lewy bodies. Why this happens is a question still awaiting an answer. Individuals who show increased numbers of these clumps are at a higher risk of developing PD or other neurodegenerative diseases.
Previous studies have demonstrated that both Lewy bodies and mitochondrial dysfunction are involved in PD. It now seems clear that these two factors are linked. Lewy bodies are thought to interfere with the way in which mitochondria (the powerhouses of the cells) function. This appears to be why Lewy bodies have a toxic effect on the brain.
Breaking research published this week in Science Translational Medicine takes a new look at Lewy bodies and their function in the etiology of PD.
The research, carried out by Dr. J. Timothy Greenamyre and his team at the Pittsburgh Institute for Neurodegenerative Diseases (PIND) in Pennsylvania, set out to understand how Lewy bodies exert their toxic effect on mitochondria.
They demonstrated that the alpha-synuclein within Lewy bodies attaches to a protein called
The binding of alpha-synuclein to TOM20 prevents the mitochondria from functioning at full capacity – less energy was produced, and there was a buildup of toxic cellular waste, such as reactive oxygen species.
“The effects of alpha-synuclein on mitochondria are like making a perfectly good coal-fueled power plant extremely inefficient, so it not only fails to make enough electricity but also creates too much toxic pollution.”
Dr. J. Timothy Greenamyre
This interaction between Lewy bodies and mitochondria appears to form a negative loop: Lewy bodies impair the functioning of mitochondria and, as the mitochondria function less well, it encourages the growth of Lewy bodies.
Armed with this information, the scientists searched for ways to reverse or lessen the disruptive effects of alpha-synuclein using cell cultures. They managed to find two ways of reducing the toxicity:
- Gene therapy designed to increase TOM20 production in neurons protected the cells from alpha-synuclein’s effects
- The addition of a second protein that blocked alpha-synuclein from binding to TOM20 prevented the toxic effects
Although more research is needed, Dr. Greenamyre hopes that this fresh avenue of investigation will allow new and more effective treatments to be designed. If the negative effects of alpha-synuclein on mitochondria can be reversed or at least hindered, the next wave of Parkinson’s medication might be much more effective.