Figure 2.

Synapse to network prodrome cascade. From the top-left: in the synapse, misfolded α-syn targets membranes, receptors, and crucial components of neural signalling pathways, driving synaptopathy (see Fig. 1). Loss of synapses affects synaptic communication, causing aberrant activity in individual neurons. This perturbed activity at the single neuron level, leads to the emergence of synaptic scaling mechanisms. Thus, impaired communication between neurons manifests as impaired communication within a circuit. Faulty circuit activity results in impairments at a network level. These aberrant network dynamics can then feedback to further influence synaptic function. In this model, these outcomes synergize to give rise to prodromal clinical manifestations including motor, sensory, and cognitive decline in α-synucleinopathies.