The mechanisms of white matter injury and immune system crosstalk in promoting the progression of Parkinson's disease: a narrative review

Abstract

Parkinson's disease (PD) is neurodegenerative disease in middle-aged and elderly people with some pathological mechanisms including immune disorder, neuroinflammation, white matter injury and abnormal aggregation of alpha-synuclein, etc. New research suggests that white matter injury may be important in the development of PD, but how inflammation, the immune system, and white matter damage interact to harm dopamine neurons is not yet understood. Therefore, it is particularly important to delve into the crosstalk between immune cells in the central and peripheral nervous system based on the study of white matter damage in PD. This crosstalk could not only exacerbate the pathological process of PD but may also reveal new therapeutic targets. By understanding how immune cells penetrate through the blood-brain barrier and activate inflammatory responses within the central nervous system, we can better grasp the impact of structural destruction of white matter in PD and explore how this process can be modulated to mitigate or combat disease progression. Microglia, astrocytes, oligodendrocytes and peripheral immune cells (especially T cells) play a central role in its pathological process where these immune cells produce and respond to pro-inflammatory cytokines such as tumor necrosis factor (TNF-α), interleukin-1β(IL-1β) and interleukin-6(IL-6), and white matter injury causes microglia to become pro-inflammatory and release inflammatory mediators, which attract more immune cells to the damaged area, increasing the inflammatory response. Moreover, white matter damage also causes dysfunction of blood-brain barrier, allows peripheral immune cells and inflammatory factors to invade the brain further, and enhances microglia activation forming a vicious circle that intensifies neuroinflammation. And these factors collectively promote the neuroinflammatory environment and neurodegeneration changes of PD. Overall, these findings not only deepen our understanding of the complexity of PD, but also provide new targets for the development of therapeutic strategies focused on inflammation and immune regulation mechanisms. In summary, this review provided the theoretical basis for clarifying the pathogenesis of PD, summarized the association between white matter damage and the immune cells in the central and peripheral nervous systems, and then emphasized their potential specific mechanisms of achieving crosstalk with further aggravating the pathological process of PD.

Keywords: Parkinson’s disease; T cells; immune modulation; microglia; oligodendrocytes; white matter damage.

Figure 1

Immunoinflammatory manifestations of Parkinson’s disease (PD): (1) white matter damage. Abnormal aggregation of α-synuclein protein leads to white matter degeneration and neuronal injury. (2) Activated microglia. White matter damage and overexpression of α-synuclein activate microglia, resulting in the production of pro-inflammatory factors that cause neuronal injury and death. (3) Antigen presentation by activated microglia, leading to activation of CD4⁺ T cells and release of inflammatory cytokines such as IFN-γ, which exert cytotoxic effects on dopaminergic neurons. (4) Release of IL-1β, TNF-α, and IFN-γ by activated microglia promotes the transformation of A2 astrocytes into A1 astrocytes. (5) Under conditions of tissue ischemia and hypoxia, axons, and neuroglia in the white matter release various neurotransmitters, leading to neuronal deformation and death. (6) The abnormal aggregation of α-syn in oligodendrocytes simultaneously activates microglia, which release a large quantity of inflammatory mediators, promoting further abnormal activation of oligodendrocytes. This process leads to myelin defects and white matter damage, impacting neuronal function.