Phosphorylated α-synuclein aggregated in Schwann cells exacerbates peripheral neuroinflammation and nerve dysfunction in Parkinson’s disease through TLR2/NF-κB pathway

Abstract

To investigate the mechanism of peripheral neuropathy in Parkinson’s disease (PD), we prepared a PD mice model by long-term exposure of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mimic PD pathology in humans and the sciatic nerves were taken for further research. It turned out that phosphorylated α-synuclein (p-α-syn) was significantly deposited in Schwann cells (SCs) of sciatic nerves possibly contributing to degenerated myelin SCs and atrophied axons in MPTP group. Further analysis confirmed that toll-like receptors (TLRs) were implicated with PD peripheral neuropathy, in which TLR2 exhibits the predominant expression. Increased expression of inflammatory factors about TLR2/nuclear factor kappa-B (NF-κB) pathway was noted in MPTP group compared to saline group, with proteins on other pathways showing no changes. Moreover, MPTP-challenged mice exhibited worse motor ability and damaged nerve conduction, implicating that p-α-syn neurotoxicity might be relevant to impairments of motor and sensory nerves. After the treatment of CU-CPT22, a TLR2 antagonist, p-α-syn accumulation, motor and sensory function were ameliorated in CU-CPT22 combined with MPTP group. Thus, we demonstrated that pathological p-α-syn might combine TLR2 to affect SCs activation, inflammatory response as well as motor and sensory function through TLR2/nuclear factor kappa-B (NF-κB) signaling pathway. This study firstly demonstrates a novel mechanism of p-α-syn accumulated in SCs of peripheral nerves, which extends our understanding on SCs-mediated peripheral neuroinflammation related to TLR2/NF-κB signaling pathway and sheds light on potential new therapeutic avenues for PD.

Blood Markers of Inflammation, Neurodegeneration, and Cardiovascular Risk in Early Parkinson's Disease

“…FGF5 and β‐NGF are both known to act as trophic factors for nerve fibers in the peripheral nervous system, and FGF5 is upregulated in Schwann cells after peripheral nerve injury 26 . In PD, α‐synuclein aggregation occurs mainly in neurons with high energy turnover and also in less myelinated axons, which could potentially exacerbate peripheral neuroinflammation 27,28 . The upregulated levels of growth factors could also be seen as a compensation to support regenerative processes.…”

“…26 In PD, α-synuclein aggregation occurs mainly in neurons with high energy turnover and also in less myelinated axons, which could potentially exacerbate peripheral neuroinflammation. 27,28 The upregulated levels of growth factors could also be seen as a compensation to support regenerative processes. β-NGF has neuroprotective effects in cholinergic neurons that project to the cerebral cortex and hippocampus.…”

Dopamine, Immunity, and Disease

“…Neurotoxicity is mainly mediated by the production of ROS and the secretion of inflammatory cytokines such as TNF- α , IL-6 and IL-1 β , which are elevated in the brain, cerebrospinal fluid (CSF), and serum in PD patients ( Boka et al, 1994 ; Mogi et al, 1994 ; Müller et al, 1998 ; Imamura et al, 2005 ; Karpenko et al, 2018 ). The presence of ROS can exacerbate α -synuclein aggregation ( Scudamore and Ciossek, 2018 ), and α -synuclein itself can activate microglia and astrocytes by binding to TLRs ( Fellner et al, 2013 ; Kim et al, 2013 ; Daniele et al, 2015 ; Kouli et al, 2020 ; Sun et al, 2021 ) that are increased in PD brains ( Shin et al, 2015 ; Dzamko et al, 2017 ; Maatouk et al, 2018 ; Ping et al, 2019 ). Increased TLR activation drives inflammation through NF- κ B ( Mogi et al, 2007 ; Reynolds et al, 2008 ; Pranski et al, 2013 ) and activates the inflammasome, which has been increasingly linked to PD pathology ( Gordon et al, 2018 ; von Herrmann et al, 2018 ).…”

Oligomeropathies, inflammation and prion protein binding

“…TLR-2, involved in the reversible neuronal dysfunction and glial activation induced by α-synOs is consistent with findings suggesting a key role for TLR-2 in synucleinopathies. The biological activity of α-syn in various forms was associated with TLR-2 in the CNS and periphery ( Dutta et al, 2021 ; Scheiblich et al, 2021 ; Sun et al, 2021a ; Xia et al, 2021 ). It has also been shown that α-synOs released by neurons can be considered endogenous agonists of TLR-2 on microglial cells ( Kim et al, 2013 ) and later the same group showed that the inactivation of TLR-2 induced autophagy and increased the clearance of α-synOs in transgenic mice and in vitro models.…”