Increased Immune Activation by Pathologic α-Synuclein in Parkinson's Disease

Area of Science:

• Neuroimmunology
• Neurodegeneration

Background:

• Excessive inflammation in the central nervous system (CNS) and periphery contributes to neurodegeneration and parkinsonism.
• Immune responses in Parkinson disease (PD) patients are dysregulated, showing heightened inflammation to non-specific triggers.
• The role of pathological alpha-synuclein (α-synuclein) as a specific trigger for excessive inflammation in PD remains unclear.

Purpose of the Study:

• To investigate the immune response of human monocytes and microglial cells to pathological forms of α-synuclein.
• To assess cytokine release upon exposure to α-synuclein.
• To determine if α-synuclein pathology specifically triggers inflammatory responses in PD.

Main Methods:

• Primary human monocytes and a microglial cell line (BV2) were exposed to pathological α-synuclein.
• Cytokine release was measured to assess immune activation.
• Extracellular vesicles (EVs) and their role in α-synuclein uptake and immune activation were investigated.
• Monocyte responses from PD patients and healthy controls were compared.
• A mouse model was used to study the in vivo effects of CNS α-synuclein pathology on peripheral monocytes.

Main Results:

• Pathological α-synuclein (mutations, aggregation) robustly activates human monocytes and microglial cells.
• Immune cell activation by α-synuclein is conformation-dependent, with fibrillation and early onset mutations showing the strongest effect.
• Extracellular vesicles potentiate α-synuclein immune cell activation, possibly by enhancing uptake.
• Blood EVs from PD patients induce stronger monocyte activation than those from healthy controls.
• Monocytes from PD patients exhibit dysregulated and hyperactive responses to pathological α-synuclein.
• CNS α-synuclein pathology induces peripheral monocyte dysregulation in a mouse model.

Conclusions:

• α-synuclein pathology and monocyte dysregulation in Parkinson disease likely collaborate to drive excessive inflammatory responses.
• Pathological α-synuclein acts as a specific trigger for heightened inflammation in PD.
• These findings highlight the neuroinflammatory mechanisms underlying Parkinson disease pathogenesis.