Dissecting the mechanisms of Parkinson's
In Europe alone there are millions of patients suffering from PD, a degenerative disorder of the central nervous system. Disease pathogenesis has been associated with neuronal cell death and a failure of plasticity processes occurring at the corticostriatal synapse. Synapses are sites where nerve cells have the ability to modulate their signal transduction efficiency depending on the outside signals they receive. The EU-funded 'Restorative plasticity at corticostriatal excitatory synapses' (REPLACES) project aimed to characterise the synapses in PD and identify novel therapeutic interventions. Several aspects of synaptic plasticity and neurophysiology were investigated with emphasis on the basal ganglia system. This part of the brain is responsible for voluntary movement and procedural learning. Partners studied the mechanisms implicated in synaptic plasticity and identified a number of molecular determinants. The experimental axis was based on the knowledge that induction of synaptic plasticity in the striatum requires interaction between dopamine and glutamate receptors. To characterise synaptic plasticity changes in PD, a novel in vivo model was used based on targeted overexpression of the protein alpha-synuclein. The hypothesis was that accumulation of alpha-synuclein interferes with synaptic signal transmission and contributes to neuronal dysfunction and PD development. Detailed analysis of the neurodegenerative changes induced by overexpression of alpha-synuclein was performed alongside characterisation of the pre- and post-synaptic compartments. Results showed that alpha-synuclein blocked the synaptic plasticity associated with memory and motor function. The REPLACES study wished to extend their pre-clinical work findings in human subjects and developed a method for magnetically stimulating the brain to measure synaptic plasticity. Cell permeable peptides demonstrated their therapeutic potential by restoring the composition of synapses and in turn striatal functions in animal disease models. Apart from expanding our fundamental knowledge on synaptic plasticity in health and disease, REPLACES has also proposed strategies for ameliorating disease pathology. Given the socioeconomic impact of PD and brain disorders in general, translation of the study findings to clinical practice will benefit millions of PD sufferers.
