Parkinson’s disease (PD) is a progressive disease that affects the brain. It is caused by a loss of brain cells in a specific region of the brain causing three main symptoms; slow movement, tremor (shaking) and rigidity of muscles. However, PD affects everyone differently and there are a lot of other symptoms that people can experience including; loss of smell, problems with sleep, depression, anxiety and memory problems, to name a few.
In PD, we see a build-up of a protein (building block) called alpha synuclein. Alpha synuclein exists in everyone’s brain but its normal function isn’t properly understood yet. However, in PD, alpha synuclein forms clumps, known as oligomers (smaller clumps) or fibrils (larger clumps). It is thought that the oligomers are more toxic to the brain whereas the fibrils, although larger, are the brain’s way of protecting itself from the toxicity of oligomers. Abnormal clumping of alpha synuclein is also seen in other diseases, collectively known as alpha synucleinopathies.
All cells need energy to survive, and this is produced by the mitochondria, which act like batteries. It is known in PD that the mitochondria don’t work properly, therefore the brain cells aren’t getting the energy that they require to survive.
This study was investigating alpha synuclein oligomers and their impact at the mitochondria. They began using cells grown in a dish that over-expressed alpha synuclein linked to a protein that luminesces under certain conditions. They found that over 72 hours, there was an increase in luminescence, meaning an increase in alpha synuclein oligomers and these were specifically at the mitochondria. As alpha synuclein oligomers increased, the levels of another protein, Sirtuin 3, decreased. Sirtuin 3 is important for modifying mitochondrial proteins once they have been produced. The researchers then looked at two more proteins that Sirtuin 3 is known to modify and found that the expression of the modified version of these proteins were decreased when there was high alpha synuclein oligomer expression. However, using a compound called AICAR, they were able to rescue this decreased expression to near normal levels.
The mitochondria form a vast network inside a cell and are constantly fusing and dividing in order to match the energy requirements of different parts of the cell. There are many proteins involved in this process but the researchers focussed on one, DRP1, which is involved in mitochondrial fission (the division of 1 mitochondrion into two mitochondria). DRP1 is usually found within the fluid part of the cell (cytoplasm), however they found that when there was increased alpha synuclein oligomers, DRP1 moved from the cytoplasm to the mitochondria. This suggests that the alpha synuclein oligomers caused an increase in mitochondrial division, meaning a more fragmented network which can lead to dysfunction.
The researchers moved on to using a more sophisticated model, a rat. Cell work is an important tool for researchers to use initially, however they can’t give us information about a whole biological organism. Rats were injected with alpha synuclein into the right hand brain region affected by PD. As expected, they found increased alpha synuclein and decreased Sirt3 in the brain region injected when compared to the same region on the opposite side. This supports the data from their cell model.
Finally, they used human post-mortem brain tissue donated from healthy individuals (controls) and people with a range of alpha synucleinopathies (patients). Patients were found to have decreased Sirt3 levels compared to controls. Interestingly, the researchers discovered that there was no difference in total alpha synuclein between the controls and patients, however they did identify an increase in alpha synuclein at the mitochondria in patients. Also, patients were found to have decreased levels of Drp1 in the cytosol and increased levels at the mitochondria, which matches their findings in the cell and rat model.
The researchers concluded that an increase in alpha synuclein oligomers correlates with a decrease in Sirt3 expression and function at the mitochondria. This leads to alterations in other proteins, affecting their roles. Overall, this is believed to contribute to the mitochondrial dysfunction seen in PD and other alpha synucleinopathies and Sirt3 could become a promising therapeutic target for the treatment of these conditions.