Pathological pathways in Parkinson's disease
Neurodegenerative disorders are a major health issue in Europe, especially with the increase in the ageing population. Alpha-synuclein (ASYN) is a pre-synaptic neuronal protein of uncertain function that under physiological conditions is a monomer with no apparent native structure. In Parkinson's disease (PD), ASYN misfolds into aggregates and concentrates in Lewy bodies, the hallmark of the disease. The observed toxicity of ASYN in PD is considered to be a result of its capacity to oligomerise and aggregate. Cellular and animal models of ASYN pathology recapitulate human PD showing neuronal and neurological dysfunction. In familial PD, the ASYN gene exhibits point mutations and multiplications, indicating that excess wild-type ASYN also leads to PD. As a result, modifying the aggregation of ASYN should be a useful therapeutic approach in PD. The scope of the EU-funded 'Academic-industrial training network on alpha-synuclein-related brain diseases' (NEURASYNC) project was to bring ASYN biology experts under the same umbrella. The ultimate goal was to advance knowledge in the field and ultimately offer solutions to patients suffering from synucleinopathies. A considerable part of the work was also dedicated to training new scientists in scientific and complementary skills who could continue working in the field. Scientists determined the structure of ASYN and found that it associates with high-density lipoprotein(HDL)to get transported across the blood-brain barrier. This finding suggests that lipid-bound ASYN could be used as a biomarker for PD. Although ASYN aggregation is tightly linked with PD, there is no unequivocal evidence on its mechanism of action. To provide mechanistic insight, the consortium developed various ASYN rodent models that over expressed the human protein. Functional analyses indicate that ASYN species induce cognitive decline by impairing neurotransmission and synaptic plasticity. With respect to therapy, scientists identified therapeutic targets, molecules with a neuroprotective action and modulators of ASYN toxicity. Collectively, these findings pave the way for drug discovery for the treatment of PD and other neurodegenerative disorders.
Keywords
Parkinson's disease, neurodegenerative disorders, alpha synuclein, brain diseases
