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Protein Going Wrong Leads to Nerve Cell Death in Parkinson’s Disease

Scientists at the Francis Crick Institute, UCL and the University of Edinburgh have uncovered how a build-up of harmful protein starts to happen within neurons, ultimately causing cell death in Parkinson’s disease.
The Edinburgh Team and Funding, an oil painting and mitochondria

By looking at how, where and why this build-up happens, the work provides unique insight into a key biological process driving Parkinson’s.

Parkinson’s is a progressive neurodegenerative disease that causes tremor, slowing of movements and stiffness, and can progress to cause neuropsychiatric, autonomic and cognitive problems. It affects around 145,000 people in the UK, with this expected to increase as more people live longer. Parkinson’s is caused by a loss of neurons in specific parts of the brain, and in affected nerve cells, a protein called alpha synuclein misfolds and clumps. But the mechanisms behind this are not yet fully understood.

In their paper, published in Nature Neuroscience, the researchers developed a new sensitive approach to study what happens to alpha-synuclein, during the earliest stages of disease. Using neurons derived from cells donated by people with inherited forms of Parkinson’s, as well as healthy individuals, the team were able to visualise where, why and how this protein starts to misfold and clump inside nerve cells.

The interdisciplinary team of neurologists, chemists and structural biologists found that alpha-synuclein contacts membranes, or linings, of structures within nerve cells. One of these membranes, the mitochondrial membrane, is able to trigger the misfolding and clumping of alpha-synuclein. The protein clumps then collect heavily on the surface of mitochondria, part of the cell responsible for generating energy. Here, they damage the surface, causing holes to form on the membrane, and interfere with the mitochondria’s ability to generate energy. As more of these clumps gather on the surface, this finally leads to the release of death signals from the mitochondria to the rest of the cell, and the neuron dies.

While there are various sub-types of Parkinson’s, this protein is known to misfold and clump together in all types. When neurons are healthy, the misfolded proteins are constantly cleared and removed from the cell. It is thought that, as people age, the process of removing this harmful protein can slow down.

There has been huge progress in understanding protein misfolding, but the major challenge has been to study the first stages of this process inside the human cell within which it occurs in disease. Our study provides insights into what is happening in the earliest stages when proteins start to misfold, and how they affect the health of the cell. This provides an important piece of the puzzle in understanding the biological mechanisms driving Parkinson’s.

Sonia Gandhi, lead author and Senior Group Leader at the Crick, and Professor of Neurology at UCL Queen Square Institute of Neurology,

We have known for some time that the mitochondria are abnormal in Parkinson’s, but it has not been clear why. This work connects where proteins misfold with how they induce mitochondrial damage, and cause cell death.

Professor Andrey Abramov, from UCL QS ION and co-lead author

Our study used neurons derived from cells taken from people with Parkinson’s, meaning the neurons we worked with had the same genetic make-up and characteristics as diseased cells in patients. This means we can be more confident that our work reflects what is happening in neurons in the body.

Minee Choi, first author and senior post-doctoral research fellow at the Crick

It’s fantastic that we have been able to use a range of state-of-the-art biophysical techniques to study how proteins misfold and cause damage in extremely complex biological samples. Our findings shed light on the very earliest events in Parkinson’s, processes that are only visible using extremely sensitive detection approaches.

Mathew Horrocks, co-lead author and senior lecturer in Biophysical Chemistry at the University of Edinburgh School of Chemistry

The innovative new method the researchers developed could also be used to study how other forms of proteins misfold in other neurodegenerative diseases and in a range of other types of cells, including glial cells which are involved in neurodegenerative diseases.

The team’s work continues in trying to understand how protein misfolding in other cellular locations affects the function and health of the cell. Furthermore they are able to test out new therapeutics to reduce protein misfolding and see whether that can rescue a diseased cell in culture.

The work at the University of Edinburgh was funded by the Rosetrees Trust, Alzheimer’s Research UK, OPTIMA CDT, and a kind donation from Alumnus Dr Jim Love.

Thursday, September 1, 2022