Phosphorylated \u03b1-synuclein aggregated in Schwann cells exacerbates peripheral neuroinflammation and nerve dysfunction in Parkinson\u2019s disease through TLR2/NF-\u03baB pathway

Li Sun,Jing Wu,Ming Lu,Yi Fan,Zhe Rong,Ye Wang,Wen-Wen Jiang,Ke-Zhong Zhang,Yong-Sheng Yuan

doi:10.1038/s41420-021-00676-w

Li Sun, Jing Wu + Show 7 more

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https://doi.org/10.1038/s41420-021-00676-w

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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.

Highlights

Parkinson’s disease (PD) is a complicated progressive neurodegenerative disease characterized by loss of dopaminergic (DA)neurons in the substantia nigra pars compacta (SNpc) and overactivated glial cells, as well as the accumulation of α-synuclein [1, 2]
Swollen even demyelinated Schwann cells (SCs) and degenerative axons of sciatic nerve were noted in MPTP group (Fig. 1C)
Inflammation signaling network of Differentially expressed genes (DEGs) suggested that 11 upregulated and 3 downregulated genes were closely linked with toll-like receptors (TLRs) pathway (Fig. 3D), which was consistent with researches about connections between PD and neuroinflammation [20,21,22]

Summary

Introduction

Parkinson’s disease (PD) is a complicated progressive neurodegenerative disease characterized by loss of dopaminergic (DA)neurons in the substantia nigra pars compacta (SNpc) and overactivated glial cells, as well as the accumulation of α-synuclein (αsyn) [1, 2]. Recent researches revealed that except the central nervous system (CNS), p-α-syn exerts critical influence on the peripheral nervous system (PNS) during PD of early stage. It has been known that p-α-syn can be detected in dermal nerves, enteric nerves, autonomic nerves, mesenteric sympathetic ganglia, stellate ganglion, paravertebral sympathetic ganglia and epicardial plexus in PD onset [5,6,7,8,9]. The abnormal p-α-syn deposition evokes systemic inflammatory response, which is a trigger for PD and exacerbates subsequent DA degeneration [10]. Lipopolysaccharide of low doses in mice induced the pro-inflammatory profile of the brain, steadily causing increased tumor necrosis factor alpha (TNF-α) levels, activated microglia, reduced brain-derived neurotrophic factor and DA levels [11]. Chronic inflammation increased activity of monoamine oxidase B conferring susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

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