Parkinson's disease is a devastating neurodegenerative disease in which nerve cells in the brain gradually die. For years, researchers have known that Parkinson's disease is associated with a build-up of alpha-synuclein protein inside brain cells.
Alpha-synuclein has a normal function, but when it starts to misfold and clump together, it causes nerve cells to die. How these alpha-synuclein protein clumps cause nerve cells to die has been a mystery.
A new study, published in Nature Communications, is making the biology of Parkinson's disease less of a mystery. The study answers several important questions: Which are the toxic species of the protein alpha-synuclein and what is the structure that makes it toxic; and how a misfolded protein might lead to cell death.
Using a combination of detailed cellular and molecular approaches to compare healthy and clumped forms of alpha-synuclein, an international, interdisciplinary team of scientists deciphered how the protein clumps are toxic to nerve cells. Led by researchers at the UK's Francis Crick Institute and the University College London, the study also involved collaborators from NYU College of Dentistry, University of Cambridge, University of Edinburgh, and others in Qatar, Russia, and Uzbekistan.
The researchers made different forms of alpha-synuclein and used single molecule biophysical methods to characterize their structure. They then tested the effects of these different aggregates of alpha-synuclein on whole cells and on isolated mitochondria, the energy powerhouses of cells.
Using a combination of single cell imaging, mitochondrial electrophysiology, and super-resolution microscopy, the researchers showed how the clumps of alpha-synuclein moved to the mitochondria in cells and came very close to the protein that generates the energy in the cell, ATP synthase. When these two proteins interact, the abnormal aggregates induce damage to the membranes and proteins in the mitochondria. This leads to a major event in the mitochondria in which a megachannel opens up, causing the mitochondria to swell and burst, and releasing chemicals that tell the cell to die.
The researchers then demonstrated that this mechanism was relevant in humans. Utilizing stem cell biology advances, the researchers took skin cells from patients with a form of early-onset Parkinson's disease caused by mutations in the gene alpha-synuclein. They turned the skin cells into stem cells, which were then chemically guided into becoming neurons – human brain cells derived from patients themselves that could be studied. This cutting-edge technique provides a valuable insight into the earliest stages of neurodegeneration – something that brain scans and post-mortem analysis cannot capture.
In these human brain cells, the researchers were also able to confirm that the alpha-synuclein formed aggregates that went to mitochondria and opened the gateway to death through the same megachannel opening.
The researchers note that their findings add to our growing understanding of the causes of Parkinson's and other neurodegenerative diseases and could influence drug design in the future.
"Our findings can help the pharmaceutical industry to recognize which is the 'toxic' form of the alpha-synuclein protein to target. This is particularly important because many therapies are being developed against alpha-synuclein," said Evgeny Pavlov, PhD, assistant professor of basic science and craniofacial biology at NYU College of Dentistry and a coauthor on the study. "It also highlights the importance of treating patients with these therapies at the time that they will be forming the toxic aggregates in their brain."
The study was conducted by a highly interdisciplinary team of scientists from many different scientific fields: physical chemistry, biophysics, stem cell biology, and electrophysiology. The paper 'α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson's disease' was published June 12 in Nature Communications.