α-Synuclein induces prodromal symptoms of Parkinson’s disease via activating TLR2/MyD88/NF-κB pathway in Schwann cells of vagus nerve in a rat model

Abstract

Background Increasing evidence suggests that patients with Parkinson's disease (PD) present with peripheral autonomic dysfunction (AutD) that even precedes motor deficits, through which α-synuclein can spread to the central nervous system. However, the pathological mechanisms underlying AutD in prodromal PD remain unclear. Here, we investigated the role of α-synuclein and its interplay with the activation of Schwann cells (SCs) of the vagus nerve in AutD. Methods Rats were subjected to injection with adeno-associated viruses containing the human mutated A53T gene (AAV-A53T) or an empty vector into the left cervical vagus nerve and evaluated for gastrointestinal symptoms, locomotor functions, intestinal blood flow, and nerve electrophysiology. Further, we examined the impact of α-synucleinopathy on vagus nerves, SCs, and central nervous system neurons using electron microscopy, immunofluorescence, immunohistochemistry, and western blot. Finally, the role of Toll-like receptor 2 (TLR2) in regulating the neuroinflammation in the vagus nerve via MyD88 and NF-κB pathway was determined using genetic knockdown. Results We found that rats injected with AAV-A53T in the vagus nerve exhibited prominent signs of AutD, preceding the onset of motor deficits and central dopaminergic abnormalities by at least 3 months, which could serve as a model for prodromal PD. In addition, reduced intestinal blood flow and decreased nerve conduction velocity were identified in AAV-A53T-injected rats, accompanied by disrupted myelin sheaths and swollen SCs in the vagus nerve. Furthermore, our data demonstrated that p-α-synuclein was deposited in SCs but not in axons, activating the TLR2/MyD88/NF-κB signaling pathway and leading to neuroinflammatory responses. In contrast, silencing the TLR2 gene not only reduced inflammatory cytokine expression but also ameliorated vagal demyelination and secondary axonal loss, consequently improving autonomic function in rats. Conclusions These observations suggest that overexpression of α-synuclein in the vagus nerve can induce symptoms of AutD in prodromal PD, and provide support for a deeper understanding of the pathological mechanisms underlying AutD and the emergence of effective therapeutic strategies for PD.

The Synergistic Effect Study of Lipopolysaccharide (LPS) and A53T-α-Synuclein: Intranasal LPS Exposure on the A53T-α-Synuclein Transgenic Mouse Model of Parkinson’s Disease

“…Studies have con rmed that degenerative DAnergic neurons could release abnormally aggregated α-synuclein into the intercellular space, which was further phagocyted by microglia, leading to the microglial activation and release of in ammatory mediators, thus further ampli ed the in ammatory reaction by α-synuclein, thereby promoting the internalization and degradation of this protein [43]. Further in vivo and in vitro studies showed that aggregated and nitrated α-synuclein induced by in ammation could signi cantly activate microglia to NF-κB activation [44,45]. A recent study found intranasal LPS could induce microglial activation, in ammatory cytokine expression in the OB and regulate α-synuclein pathology in the OB, striatum and SN via IL-1β/IL-1R1 signaling [46].…”

Retinal Alterations Predict Early Prodromal Signs of Neurodegenerative Disease

“…It is well recognized that PD is characterized by the deposition of α-synuclein in the substantia nigra. However, it is noteworthy that α-synuclein deposition may also affect the entire CNS as well as the autonomic nervous system, which may predict prodromal symptoms of Parkinson's disease [229,230].…”

Parkinson’s disease and gut microbiota: from clinical to mechanistic and therapeutic studies

“…Gut microbes influence TLR2 expression, and TLR2 recognizes bacterial products such as lipoteichoic acid, lipoproteins, peptidoglycans, and bacterial amyloid (e.g., curli protein) [159]. By binding and activating TLR2, curli increases intracellular α-syn, triggering a neuroinflammatory response via the TLR2/ MyD88/NF-κB pathway [160,161]. Similarly, activation of TLR2 in the brains of PD patients increases proinflammatory cytokine levels and microglial recruitment and amplifies neuroinflammation and α-syn expression.…”