Linking alpha-synuclein-induced synaptopathy and neural network dysfunction in early Parkinson's disease

Brain Communications(2022)

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摘要
A common conceptualization of Parkinson's disease is that alpha-syn aggregation leads to cell death, followed by symptomology. Here, Kulkarni et al. propose a novel 'synapse to network prodrome cascade' wherein in the absence of overt cell death, pathological alpha-syn induces synaptic loss and aberrant network activity, underlying prodromal non-motor symptoms. The prodromal phase of Parkinson's disease is characterized by aggregation of the misfolded pathogenic protein alpha-synuclein in select neural centres, co-occurring with non-motor symptoms including sensory and cognitive loss, and emotional disturbances. It is unclear whether neuronal loss is significant during the prodrome. Underlying these symptoms are synaptic impairments and aberrant neural network activity. However, the relationships between synaptic defects and network-level perturbations are not established. In experimental models, pathological alpha-synuclein not only impacts neurotransmission at the synaptic level, but also leads to changes in brain network-level oscillatory dynamics-both of which likely contribute to non-motor deficits observed in Parkinson's disease. Here we draw upon research from both human subjects and experimental models to propose a 'synapse to network prodrome cascade' wherein before overt cell death, pathological alpha-synuclein induces synaptic loss and contributes to aberrant network activity, which then gives rise to prodromal symptomology. As the disease progresses, abnormal patterns of neural activity ultimately lead to neuronal loss and clinical progression of disease. Finally, we outline goals and research needed to unravel the basis of functional impairments in Parkinson's disease and other alpha-synucleinopathies.
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关键词
neuron, synapse, oscillation, neural network, prodrome
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