Abstract
Parkinson’s Disease (PD) is a neurodegenerative disease that affects the elderly. It is associated with motor dysfunction due to the accumulation of misfolded or aggregated fibrillar alpha-synuclein (α-syn) in the mid-brain. Current treatments are mainly focused on relieving the symptoms but are accompanied by side effects and are limited in halting disease progression. Increasing evidence points to peripheral immune cells underlying disease development, especially T cells contributing to α-syn-related neuroinflammation in PD. The onset of these cells is likely mediated by dendritic cells (DCs), whose role in α-syn-specific responses remain less studied. Moreover, Traditional Chinese medicine (TCM)-derived compounds that are candidates to treat PD may alleviate DC-T cell-mediated immune responses. Therefore, our study focused on the role of DC in response to fibrillar α-syn and subsequent induction of antigen-specific T cell responses, and the effect of TCM Curcumin-analog C1 and Tripterygium wilfordii Hook F-derived Celastrol. We found that although fibrillar α-syn did not induce significant inflammatory or T cell-mediating cytokines, robust pro-inflammatory T cell responses were found by co-culturing fibrillar α-syn-pulsed DCs with α-syn-specific CD4+ T cells. Celastrol, but not C1, reduced the onset of pro-inflammatory T cell differentiation, through promoting interaction of endosomal, amphisomal, and autophagic vesicles with fibrillar α-syn, which likely lead to its degradation and less antigen peptides available for presentation and T cell recognition. In conclusion, regulating the intracellular trafficking/processing of α-syn by DCs can be a potential approach to control the progression of PD, in which Celastrol is a potential candidate to accomplish this.
Highlights
Parkinson’s Disease (PD) is the second most common neurodegenerative disease in the world, affecting approximately 10 million people worldwide who are aged over 60 [1]
Our results suggested that a-syn had minimal effects on inflammatory cytokine gene expression in MoDCs, but this can still be modulated by Celastrol
Neuroinflammation aroused by peripheral immune cells in response to abnormal a-syn has been highlighted in the progression of PD [30, 61]
Summary
Parkinson’s Disease (PD) is the second most common neurodegenerative disease in the world, affecting approximately 10 million people worldwide who are aged over 60 [1]. A-Synuclein (a-syn) is a presynaptic protein that is expressed abundantly in the mammalian brain and peripheral tissues [3]. One pathological hallmark of PD is the accumulation of misfolded a-syn protein inclusions forming Lewy bodies inside the neuronal cells that are caused by either familial inherited gene mutations or idiopathic factors [5–7]. The abnormal a-syn in the shape of the b-sheet structure serve as nucleation sites, which further recruit endogenous monomeric a-syn, convert into soluble oligomeric form that at a later stage, aggregate into insoluble fibrillar form [8, 9]. It is proposed that accumulation of oligomeric or fibrillar a-syn leads to dopaminergic neuronal cell death and activates the brain resident microglia causing neuroinflammation [10, 11]. Dysregulated and prolonged neuroinflammation will lead to more neuronal cell death and compromise the integrity of the blood–brain barrier (BBB), favor the recruitment and infiltration of peripheral immune cells which could worsen the disease [12–14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
