Scholarlink

Background <p>The accumulation and propagation of α-synuclein (α-syn) are hallmark features of Parkinson’s disease (PD) and related neurodegenerative disorders. O-GlcNAcylation, an abundant post-translational modification throughout the brain, is regulated by the enzymatic activity of the cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) and has been implicated in altering α-syn toxicity. Nevertheless, the interplay between modulating O-GlcNAc cycling and α-syn aggregation and the propagation of amyloid pathology is not well elucidated.</p> Methods <p>To this end, we delivered conformational strains of α-syn in the striatum of mice or neuronal and microglial co-cultured cells following pharmacologically or genetically inhibited OGT and OGA. The substantia nigra was injected with an adeno-associated viral vector coding for α-syn combined with α-syn preformed fibrils to examine α-syn-induced dopaminergic cytotoxicity. The α-syn pathology and spreading, protein O-GlcNAcylation, OGT and OGA levels, microglial inflammation, and behavioral impairments were evaluated. Furthermore, the O-GlcNAc modification and proteolysis status of α-syn under O-GlcNAc cycling modification were also assessed using a combination of approaches, including Click-iT™ O-GlcNAc enzyme labeling, sWGA pulldown, HPLC-MS/MS, and immunohistochemical analysis following proteasome and autophagy-lysosome inhibition.</p> Results <p>We found that modulation of O-GlcNAc cycling, governed by the two enzymes OGT and OGA, significantly affected α-syn aggregation, propagation, dopaminergic neuronal degeneration, and microglial inflammation. Pathological α-syn transmission to adjacent cells and anatomically connected brain regions was found to suppress recipient cellular O-GlcNAc levels, concomitant with reduced OGT expression. Pharmacological inhibition or genetic knockdown of OGT exacerbated α-syn aggregation, enhanced its intercellular transmission, and intensified NOD-, LRR-, and pyrin domain-containing 3 (NLRP3)-mediated microglial inflammation. Conversely, increasing O-GlcNAcylation via OGA inhibition ameliorated these pathological processes. Furthermore, we demonstrate that enzymatic O-GlcNAcylation significantly regulates the aggregation of fibril-induced initial dimer formation and facilitates the clearance of α-syn aggregates through autophagosome-lysosome flux.</p> Conclusions <p>These findings highlight the critical regulatory role of O-GlcNAc modification in α-syn pathology and conformational strain formation, and provide mechanical evidence that enhancing O-GlcNAc modifications alleviates pathological α-syn proteolysis by restoring autophagosome-lysosome flux.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Modulation of O-GlcNAc cycling influences α-synuclein amplification, degradation, and associated neuroinflammatory pathology

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月27日

查看全文
  • Yongzhen Miao,
  • Ting Zhang,
  • Zhuoya Ma,
  • Huanhuan Du,
  • Qipei Gu,
  • Mengni Jiang,
  • Kangping Xiong,
  • Chun-Feng Liu,
  • Hongrui Meng

摘要

Background

The accumulation and propagation of α-synuclein (α-syn) are hallmark features of Parkinson’s disease (PD) and related neurodegenerative disorders. O-GlcNAcylation, an abundant post-translational modification throughout the brain, is regulated by the enzymatic activity of the cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) and has been implicated in altering α-syn toxicity. Nevertheless, the interplay between modulating O-GlcNAc cycling and α-syn aggregation and the propagation of amyloid pathology is not well elucidated.

Methods

To this end, we delivered conformational strains of α-syn in the striatum of mice or neuronal and microglial co-cultured cells following pharmacologically or genetically inhibited OGT and OGA. The substantia nigra was injected with an adeno-associated viral vector coding for α-syn combined with α-syn preformed fibrils to examine α-syn-induced dopaminergic cytotoxicity. The α-syn pathology and spreading, protein O-GlcNAcylation, OGT and OGA levels, microglial inflammation, and behavioral impairments were evaluated. Furthermore, the O-GlcNAc modification and proteolysis status of α-syn under O-GlcNAc cycling modification were also assessed using a combination of approaches, including Click-iT™ O-GlcNAc enzyme labeling, sWGA pulldown, HPLC-MS/MS, and immunohistochemical analysis following proteasome and autophagy-lysosome inhibition.

Results

We found that modulation of O-GlcNAc cycling, governed by the two enzymes OGT and OGA, significantly affected α-syn aggregation, propagation, dopaminergic neuronal degeneration, and microglial inflammation. Pathological α-syn transmission to adjacent cells and anatomically connected brain regions was found to suppress recipient cellular O-GlcNAc levels, concomitant with reduced OGT expression. Pharmacological inhibition or genetic knockdown of OGT exacerbated α-syn aggregation, enhanced its intercellular transmission, and intensified NOD-, LRR-, and pyrin domain-containing 3 (NLRP3)-mediated microglial inflammation. Conversely, increasing O-GlcNAcylation via OGA inhibition ameliorated these pathological processes. Furthermore, we demonstrate that enzymatic O-GlcNAcylation significantly regulates the aggregation of fibril-induced initial dimer formation and facilitates the clearance of α-syn aggregates through autophagosome-lysosome flux.

Conclusions

These findings highlight the critical regulatory role of O-GlcNAc modification in α-syn pathology and conformational strain formation, and provide mechanical evidence that enhancing O-GlcNAc modifications alleviates pathological α-syn proteolysis by restoring autophagosome-lysosome flux.