Parkinson’s disease is the second most prevalent neurological condition after dementia. The disease is characterised by the abnormal accumulation in the brain of a protein called α-synuclein, as well as the loss of dopamine-producing cells in an area of the brain known as the substantia nigra. The loss of these cells causes the symptoms of Parkinson’s, including trembling, stiffness, slowness of movement and a loss of fine motor control.
“We’ve shown how inflammation within the brain is related to the development of Parkinson’s disease,” says Dr Nic Dzamko of Neuroscience Research Australia, “and we’ve identified a potential mechanism that can prevent this inflammation. It offers hope and introduces a new target for therapeutic research, which we’re now working on.”
The study, published in Acta Neuropathologica, turned pluripotent human skin cells into neuronal cells in order to understand the effects of inflammation on the brain. “Although the exact causes of Parkinson’s disease are unknown, accumulating evidence suggests that inflammation plays a strong role in the development of the disease,” Dzamko says.
The brain uses toll-like receptors (TLR) to detect pathogens and regulate inflammation arising from compromised immunity. A consequence of activating TLR is the production of α-synuclein, which is responsible for creating “clumps” of the Lewy bodies that are a hallmark of Parkinson’s disease.
“We found that a particular toll-like receptor, TLR2, is increased in neurons in post mortem PD brain tissue,” Dzamko says. “Given that neurons accumulate α-synuclein in Parkinson’s disease, our results suggest that TLR2 is of central importance in understanding how the disease starts.”
Activation of TLR2 in stem cells created an inflammatory response that increased the levels of α-synuclein, suggesting that inflammation is a cause, at least in part, of Parkinson’s disease.
“Given that we were able to find this association in the post mortem brain tissue, then model this relationship in tissue culture, we’re confident that we’ve understood a key process in the development of Parkinson’s,” Dzamko says.
The team also found that a drug that inhibits TLR2 also prevented the increased clumping of α-synuclein in the stem cell-derived neurons, suggesting it as a target for further research into therapeutic interventions. “The next stage will be to identify a drug that can be used in human trials, which acts on the pathway we’ve identified and prevents the TLR2-enabled increase in α-synuclein,” Dzamko says.