Table 2.

Outstanding questions to understand synaptic and network causes underlying the Parkinson’s disease prodrome

What is the role of glial pathology and how does it affect neural activity? What is the relationship between pathological burden, network dysfunction, and clinical manifestations? What is the role of other cellular dysfunctions (e.g. neuroinflammation, oxidative stress, mitochondrial dysfunction) on the neuropathogenesis of α-synucleinopathies? What specific cell types are functionally vulnerable to and/or aggregate α-syn pathology? Why are they vulnerable? How does activity-dependent neuropathogenesis contribute to perturbed network dynamics? Does deep brain stimulation entail long-term changes to neural networks?