Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson's Disease

Analysis of human pathology led Braak to postulate that a-synuclein (alpha-syn) pathology could spread from the gut to brain via the vagus nerve. Here, we test this postulate by assessing alpha-synucleinopathy in the brain in a novel gut-to-brain alpha-syn transmission mouse model, where pathological alpha-syn preformed fibrils were injected into the duodenal and pyloric muscularis layer. Spread of pathologic alpha-syn in brain, as assessed by phosphorylation of serine 129 of alpha-syn, was observed first in the dorsal motor nucleus, then in caudal portions of the hindbrain, including the locus coeruleus, and much later in basolateral amygdala, dorsal raphe nucleus, and the substantia nigra pars compacta. Moreover, loss of dopaminergic neurons and motor and non-motor symptoms were observed in a similar temporal manner. Truncal vagotomy and alpha-syn deficiency prevented the gut-to-brain spread of alpha-synucleinopathy and associated neurodegeneration and behavioral deficits. This study supports the Braak hypothesis in the etiology of idiopathic Parkinson's disease (PD).