Scholarlink

Background <p>Parkinson disease is a progressive neurodegenerative disorder characterized by the degeneration of dopamine neurons in the <i>substantia nigra pars compacta</i>, leading to a broad spectrum of motor and non-motor symptoms. Increasing evidence indicates that chronic inflammation and immune dysregulation are central to its pathogenesis. The activation of microglia, astrocytes, and circulating monocytes establishes a self-perpetuating cycle of inflammation and neuronal injury, positioning monocytes as a key interface between systemic and central immune responses.</p> Main text <p>The discovery of misfolded alpha-synuclein in peripheral tissues, such as the gut, olfactory mucosa and skin, supports a multisystem view of the disease, suggesting that peripheral pathology may precede and drive neurodegeneration through neuroanatomical and microbiota-mediated routes. Monocytes exhibit altered subset composition, impaired phagocytic capacity, and metabolic reprogramming involving mitochondrial and lysosomal dysfunction, partly linked to mutations in the <i>LRRK2</i> and <i>GBA1</i> genes, which further sustain inflammation and alpha-synuclein aggregation. In parallel, the disruption of the blood-brain and meningeal barriers facilitates immune cell infiltration and amplifies neuroinflammatory signalling within the brain. Elevated circulating cytokines, chemokines, and inflammasome activation reflect a primed immune state correlated with disease progression, whereas metabolic disturbances in tryptophan, purine, lipid, and microbiota-derived pathways connect peripheral metabolic imbalance to neuronal vulnerability. Finally, exosomes act as critical mediators of communication between the periphery and the brain. Owing to their ability to cross the blood-brain barrier bidirectionally, they contribute to the dissemination of alpha-synuclein and transport miRNAs that promote oxidative stress, two key mechanisms underlying Parkinson disease pathology. These features position exosomes as both promising targets for biomarker discovery and effective vehicles for the targeted delivery of therapeutic agents to the central nervous system.</p> Conclusions <p>Together, this review highlights peripheral inflammation and misfolded alpha-synuclein as pivotal contributors to neuroinflammatory mechanisms in Parkinson disease, emphasizing monocyte-related pathways as promising targets for disease monitoring and intervention.</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

Peripheral immunochemical considerations in Parkinson disease: sources, targets and crosstalk mechanisms

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月14日

查看全文
  • Alessandra Castegna,
  • Luna Laera,
  • Piergianni Moda,
  • Stefano Miglietta,
  • Mariagrazia D’Agostino,
  • Melania Ruggiero,
  • Antonia Cianciulli,
  • Francesca Martina Filannino,
  • Chiara Porro,
  • D. Allan Butterfield,
  • Maria Antonietta Panaro

摘要

Background

Parkinson disease is a progressive neurodegenerative disorder characterized by the degeneration of dopamine neurons in the substantia nigra pars compacta, leading to a broad spectrum of motor and non-motor symptoms. Increasing evidence indicates that chronic inflammation and immune dysregulation are central to its pathogenesis. The activation of microglia, astrocytes, and circulating monocytes establishes a self-perpetuating cycle of inflammation and neuronal injury, positioning monocytes as a key interface between systemic and central immune responses.

Main text

The discovery of misfolded alpha-synuclein in peripheral tissues, such as the gut, olfactory mucosa and skin, supports a multisystem view of the disease, suggesting that peripheral pathology may precede and drive neurodegeneration through neuroanatomical and microbiota-mediated routes. Monocytes exhibit altered subset composition, impaired phagocytic capacity, and metabolic reprogramming involving mitochondrial and lysosomal dysfunction, partly linked to mutations in the LRRK2 and GBA1 genes, which further sustain inflammation and alpha-synuclein aggregation. In parallel, the disruption of the blood-brain and meningeal barriers facilitates immune cell infiltration and amplifies neuroinflammatory signalling within the brain. Elevated circulating cytokines, chemokines, and inflammasome activation reflect a primed immune state correlated with disease progression, whereas metabolic disturbances in tryptophan, purine, lipid, and microbiota-derived pathways connect peripheral metabolic imbalance to neuronal vulnerability. Finally, exosomes act as critical mediators of communication between the periphery and the brain. Owing to their ability to cross the blood-brain barrier bidirectionally, they contribute to the dissemination of alpha-synuclein and transport miRNAs that promote oxidative stress, two key mechanisms underlying Parkinson disease pathology. These features position exosomes as both promising targets for biomarker discovery and effective vehicles for the targeted delivery of therapeutic agents to the central nervous system.

Conclusions

Together, this review highlights peripheral inflammation and misfolded alpha-synuclein as pivotal contributors to neuroinflammatory mechanisms in Parkinson disease, emphasizing monocyte-related pathways as promising targets for disease monitoring and intervention.