Parkinson’s disease (PD) is an increasingly common disease. People with the disease have motor symptoms including a tremor, limb shaking; slowed movements, including shuffling walk; and stiffness of muscles. There is also a loss of the dopamine nerves in people PD, which have an important role in coordinating movements. Nerves are like wires that send messages around the brain and to the body, and dopamine is one type of signal that these wires send to specific parts of the brain and body. In people with PD, α-synuclein, a type of protein (molecules that make up tissues and organs in the body), sticks together in some parts of their brain, forming big clumps, which can affect dopamine signalling. Stopping this clumping may therefore restore dopamine signalling in people with PD and alleviate some of the symptoms.
In this study, α-synuclein was put with small molecular ‘tweezers’ (called CLR01) in a tube and left for a series of days. CLR01 attaches to parts of proteins and cuts the protein, so that it can no longer be held together which means that the protein can’t function. In the tube with just α-synuclein, the protein stuck together and clumped, but in the tube that also had CLR01, α-synuclein didn’t clump together.
Similar clumping was also observed with α-synuclein in brain samples analysed from people with PD. However, when CLR01 was added to the brain samples for 10 days the protein clumping was abolished, suggesting CLR01 had broken the clumps up. In further work, dopamine nerves were made from human samples and treated with CLR01. To make the nerves, stem cells were taken from people. Stem cells are a special type of cell that can be turned into different types of cell, including nerves. The nerves they made were given a treatment that damaged them and caused a build-up of the protein α-synuclein. When CLR01 was then given to the nerves, it rescued them from the damage.
The researchers also looked in an animal model of PD. Mice of different ages (6, 12 and 18 months) were engineered to produce high levels of α-synuclein to mimic what happens in people with PD. At 6 months there was no difference in the build-up of protein in the engineered PD mice and the normal healthy mice. At 12 months, the PD mice with too much protein had problems with their movements and showed clumping of protein; this was not seen in healthy control mice. When the mice were treated with CLR01, it rescued their motor skills and decreased the protein clumping. Motor skills are things like standing and walking. In mice these were tested in two ways. Firstly, by placing them on a rotating beam and timing how long it took for them to fall off. Secondly, mice ran on a runaway and the researchers measured the placing of their feet and their stride length to determine the pattern of their movements. At 18 months, the motor symptom defects could not be rescued with CLR01, but there was a reduction in the clumping. This suggests that the effect of CLR01 on symptoms is dependent on age; at too late an age, there is too much damage to be fixed. CLR01 has potential for being used in the clinic, but more testing is needed first. CLR01 may only be useful as a treatment for those in an earlier stage of PD, before the brain is too damaged. Therefore, early diagnosis of PD in people is crucial.