Given the inadequate understanding of the biology of Parkinson's Disease (PD), pain is a typical non-motor symptom. In this study, we demonstrate that peripheral administration of mouse alpha-synuclein (-Syn) pre-formed fibrils caused retrograde trans-synaptic spreading of -Syn pathology (pSer129) across sensory neurons and dorsal nerve roots, reaching central pain processing regions, including the spinal dorsal horn and the projections of the anterolateral system in the Central Nervous System (CNS). Reduced nerve conduction velocities (sensory and motor) and degeneration of small- and medium-sized myelinated fibers were co-occurring with impaired nociceptive response and pathological peripheral to CNS propagation of -Syn aggregates along interconnected neuronal populations within sensory afferents. Our findings indicate intriguing lines of inquiry into the processes driving pain in PD, linking Tran’s neuronal propagation of -Syn disease with sensory neuron failure and neuropathic impairment.
