Synapsin III gene silencing redeems alpha-synuclein transgenic mice from Parkinson’s disease-like phenotype
Summary by Giuseppe Madaro
Background
If we could zoom in on the brain of person with Parkinson’s disease, we would notice that some of their nerve cells (neurons) contain thread-shaped clumps, known as protein aggregates. These are made of malfunctioning cellular components (proteins) that stick to one another like Lego bricks and become resistant to all the waste recycling mechanisms used by the cells. The protein aggregates found in Parkinson’s disease are mainly made up of alpha-synuclein which, in normal conditions, regulates how neurons communicate with each other and transmit electrical impulses. Over time, alpha-synuclein aggregates build up in the brains of people with Parkinson’s, damage the neurons and cause them to die. This results in the progressive loss of the ability to move, think, and learn new things.
Why is the study important?
To date, all the medications available can only alleviate the symptoms of Parkinson’s disease. However, we cannot rely on any treatments to prevent alpha-synuclein aggregation and a further loss of neurons. This study explores a strategy to stop the progression of the disease.
What did the authors do and how did they do it?
Faustini and colleagues observed that alpha-synuclein is not the only protein to form the aggregates which characterise Parkinson’s disease. Another protein involved in the transmission of nerve signals in the brain, called Synapsin III, acts as the glue which makes alpha-synuclein “Lego-bricks” even stickier. They wondered if by eliminating Synapsin III from the neurons they could reduce alpha-synuclein aggregation. To test this, they exploited the ability of a genetically modified virus to enter the neurons and hack them by interfering with how the DNA (the blueprint of a cell) is read and interpreted. The team injected the virus into the brains of mice with a mutation which causes some features of Parkinson’s disease. This blocked the production of Synapsin III in all the infected neurons.
What are the results?
Mice that received the treatment showed some consistent improvements compared to those that did not. Lowering the amount of Synapsin III in the brain reduces the formation of alpha-synuclein aggregates and protects the connections between neurons and the way they communicate with each other. This prevents mutant mice from developing the main features of Parkinson’s disease, including the loss of movement control. The same treatment provided to healthy mice had no visible side-effects, meaning that healthy neurons in mice can adapt to the lack of Synapsin III.
What do the findings mean going forward for people with the disease?
Even if the methods used in this study are still not refined enough to be safely used on humans, the authors demonstrated that Synapsin III is a promising target to focus on for the development of future drug treatment in the next few decades.
This study can be found at: https://doi.org/10.1016/j.ymthe.2022.01.021
Paper title: Synapsin III gene silencing redeems alpha-synuclein transgenic mice from Parkinson’s disease-like phenotype
Author list: Faustini G., Longhena F., Masato A., Bassareo V., Frau R., Klingstedt T., Shirani H., Brembati V., Parrella E., Vezzoli M., Nilsson K.P.R., Pizzi M., Spillantini M.G., Bubacco L., Bellucci A.
Publication details: accepted 12 January 2022, Molecular Therapy Vol. 30 No 4, April 2022, The American Society of Gene and Cell Therapy