Abstract
α-Synucleinopathies are characterized by autonomic dysfunction and motor impairments. In the pure autonomic failure (PAF), α-synuclein (α-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 α-Syn preformed fibrils (PFFs) into the stellate and celiac ganglia induces spreading of α-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 α-Syn pathology. This model may help define the mechanistic link between transmission of pathological α-Syn and the cardinal features of autonomic dysfunction in α-synucleinopathy.
Highlights
Α-Synucleinopathies are characterized by autonomic dysfunction and motor impairments
Various mouse models of α-synucleinopathy induced by exogenous inoculation of pathological α-Syn develop α-Syn pathology in different distribution patterns and clinical phenotypes predominantly related to motor dysfunction; autonomic dysfunction rarely occurs or is observed in these models
We demonstrate that inoculation of αSyn preformed fibrils (PFFs) into the stellate ganglia and celiac ganglia of TgM83+/− mice can induce transmission of pathological α-Syn through the autonomic pathway to both the central nervous system (CNS) and autonomic innervation of peripheral organs bidirectionally
Summary
Α-Synucleinopathies are characterized by autonomic dysfunction and motor impairments. We show that in TgM83+/− mice, inoculation of α-Syn preformed fibrils (PFFs) into the stellate and celiac ganglia induces spreading of α-Syn pathology only through the autonomic pathway to both the central nervous system (CNS) and the autonomic innervation of peripheral organs bidirectionally. We have generated a mouse model of pure autonomic dysfunction caused by α-Syn pathology. Various mouse models of α-synucleinopathy induced by exogenous inoculation of pathological α-Syn develop α-Syn pathology in different distribution patterns and clinical phenotypes predominantly related to motor dysfunction; autonomic dysfunction rarely occurs or is observed in these models. We demonstrate that inoculation of αSyn preformed fibrils (PFFs) into the stellate ganglia and celiac ganglia of TgM83+/− mice can induce transmission of pathological α-Syn through the autonomic pathway to both the CNS and autonomic innervation of peripheral organs bidirectionally. We have established a mouse model of pure autonomic dysfunction induced by pathological α-Syn, which will provide a valuable avenue for interrogating progression mechanisms of, and developing disease-modifying therapies for, autonomic dysfunction in αsynucleinopathy
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