Synaptic dysfunction in Parkinson's Disease: functional and ultrastructural study of the striatal synapses in an animal model of progressive parkinsonism

Abstract

This Ph.D. project involves the temporal sequence of the earliest functional and structural events in the striatal synapses in a rat model of progressive parkinsonism induced by overexpression of human ¿-synuclein (h¿-syn) with A53T mutation (rAAV-h¿-syn) in the substantia nigra compacta (SNc), before parkinsoniasn motor features appear. We have observed a sequential pattern of events. The aggregation of h¿-syn in the striatal dopaminergic terminals firstly induces deregulation of proteins affecting metabolism followed by decreased mitochondrial respiration in striatal synaptosomes. Differential analysis by proteomics revealed significant deregulated proteins from biological pathways related to synaptic function and neurotransmission. These functional and proteostatic alterations precede the structural changes and the onset of degeneration of the dopaminergic axons in the striatum that precede the loss of neuronal soma in the SNc. Lastly, homeostatic changes in glutamatergic synapses are simultaneous to the onset of the synaptic functional deficit, and dendritic spine loss is accompanied by plastic events. These last findings could represent compensatory mechanisms to maintain normal function during the onset of dopaminergic degeneration. We count with a good model of progressive synaptopathy in the dopaminergic pathway linked to the accumulation of h¿-syn, providing an excellent preclinical model to develop new synapse-targeted therapies.