Scientists from the Francis Crick Institute, UCL and the University of Edinburgh have discovered how a buildup of harmful proteins begins to occur in neurons in Parkinson’s disease, ultimately causing nerve cell death. By examining how, where and why this buildup occurs, the work provides unique insight into a key biological process underlying Parkinson’s disease.
Parkinson’s disease is a progressive neurodegenerative disease that causes tremors, slowed movement, stiffness and can progress to cause serious cognitive problems. It affects around 145,000 people in the UK, and that number is expected to rise as more people live longer.
Parkinson’s disease is caused by a loss of neurons in specific parts of the brain. In affected nerve cells, a protein called alpha-synuclein folds up and clumps together into harmful structures. The mechanisms behind this are not yet fully understood.
In their article published in Natural neuroscience Now researchers have developed a sensitive new approach to study what happens to alpha-synuclein during the early stages of the disease.
Using neurons derived from cells donated by people with inherited forms of Parkinson’s disease, as well as healthy individuals, the team was able to visualize where, why, and how this protein begins to fold and s clump together inside nerve cells.
The interdisciplinary team of neurologists, chemists and structural biologists discovered that alpha-synuclein comes into contact with the membranes, or coverings, of nerve cell structures. When it comes into contact with the membrane of the mitochondria, the part of the cell responsible for energy production, it triggers the misfolding and clumping of alpha-synuclein.
The protein clumps then accumulate strongly on the surface of the mitochondria, damaging its surface, causing holes to form on the membrane and interfering with the mitochondria’s ability to create energy. Eventually, this leads the mitochondria to release signals that cause the neuron to die.
Although there are different subtypes of Parkinson’s disease, this protein is known to fold and clump together in all types. When neurons are healthy, misfolded proteins are constantly being eliminated and removed from the cell. It is believed that as people age, the process of removing this harmful protein may slow down.
Sonia Gandhi, lead author and senior group leader at Crick, and professor of neurology at the UCL Queen Square Institute of Neurology, says: “There have been huge advances in understanding protein misfolding, but the challenge major task has been to study the first steps of this process inside the human cell.
“Our study provides insight into what happens in the early stages when proteins begin to fold and how it affects the health of the cell. This provides an important piece of the puzzle for understanding the biological mechanisms behind Parkinson’s disease.
Andrey Abramov, co-lead author and professor at the UCL Queen Square Institute of Neurology adds: “We have known for some time that mitochondria are abnormal in Parkinson’s disease, but it is unclear why. This work links where proteins misfold with how they induce mitochondrial damage and cause cell death.”
Minee Choi, first author and senior postdoctoral researcher at Crick, says: “Our study used neurons derived from cells taken from people with Parkinson’s disease, which means that the neurons we worked with had the same constitution genetics and the same characteristics as diseased cells. in patients. This means we can be more confident that our work reflects what is happening in the neurons of the body.
Matthew Horrocks, co-lead author and senior lecturer in biophysical chemistry at the University of Edinburgh, adds: “It’s fantastic that we’ve been able to use a range of cutting-edge biophysical techniques to study how proteins fold and cause damage in extremely complex biological samples Our findings shed light on the earliest events of Parkinson’s disease, processes that are only visible using extremely sensitive detection approaches.
The innovative new method developed by the researchers could also be used to study protein misfolding in other neurodegenerative diseases and cell types, including glial cells implicated in neurodegenerative diseases.
The team will continue their work by studying how protein misfolding inside cells affects cell function and health. Using their new approach, they will be able to test new therapies aimed at reducing protein misfolding and see if these therapies can restore a diseased cell to health.
Scientists discover molecular mechanisms of Parkinson’s disease
Minee L. Choi et al, Pathological structural conversion of α-synuclein at mitochondria induces neuronal toxicity, Natural neuroscience (2022). DOI: 10.1038/s41593-022-01140-3
Provided by the Francis Crick Institute
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