Autonomic ganglionic injection of α-synuclein fibrils as a model of pure autonomic failure α-synucleinopathy

alpha-Synucleinopathies are characterized by autonomic dysfunction and motor impairments. In the pure autonomic failure (PAF), alpha-synuclein (alpha-Syn) pathology is confined within the autonomic nervous system with no motor features, but mouse models recapitulating PAF without motor dysfunction are lacking. Here, we show that in TgM83(+/-) mice, inoculation of alpha-Syn preformed fibrils (PFFs) into the stellate and celiac ganglia induces spreading of alpha-Syn pathology only through the autonomic pathway to both the central nervous system (CNS) and the autonomic innervation of peripheral organs bidirectionally. In parallel, the mice develop autonomic dysfunction, featured by orthostatic hypotension, constipation, hypohidrosis and hyposmia, without motor dysfunction. Thus, we have generated a mouse model of pure autonomic dysfunction caused by alpha-Syn pathology. This model may help define the mechanistic link between transmission of pathological alpha-Syn and the cardinal features of autonomic dysfunction in alpha-synucleinopathy.