The involvement of α-synucleinopathy in the disruption of microglial homeostasis contributes to the pathogenesis of Parkinson’s disease

Abstract

The intracellular deposition and intercellular transmission of α-synuclein (α-syn) are shared pathological characteristics among neurodegenerative disorders collectively known as α-synucleinopathies, including Parkinson's disease (PD). Although the precise triggers of α-synucleinopathies remain unclear, recent findings indicate that disruption of microglial homeostasis contributes to the pathogenesis of PD. Microglia play a crucial role in maintaining optimal neuronal function by ensuring a homeostatic environment, but this function is disrupted during the progression of α-syn pathology. The involvement of microglia in the accumulation, uptake, and clearance of aggregated proteins is critical for managing disease spread and progression caused by α-syn pathology. This review summarizes current knowledge on the interrelationships between microglia and α-synucleinopathies, focusing on the remarkable ability of microglia to recognize and internalize extracellular α-syn through diverse pathways. Microglia process α-syn intracellularly and intercellularly to facilitate the α-syn neuronal aggregation and cell-to-cell propagation. The conformational state of α-synuclein distinctly influences microglial inflammation, which can affect peripheral immune cells such as macrophages and lymphocytes and may regulate the pathogenesis of α-synucleinopathies. We also discuss ongoing research efforts to identify potential therapeutic approaches targeting both α-syn accumulation and inflammation in PD.

Nicotinic Acetylcholine Receptors in Glial Cells as Molecular Target for Parkinson’s Disease

“…Overall, it may be concluded that microglia play a pivotal role in the spread of α-Syn and the eventual pathophysiology of synucleinopathies, including those related to circadian rhythm dysfunction. Therefore, extensive effort is expended in elucidating the molecular mechanism(s) of microglial interactions with α-Syn in the hope of identifying novel therapeutic targets for prominent neurodegenerative diseases, including PD [85,86]. It is also worth mentioning that TLR 4 is required for the α-Syn-dependent activation of microglia [92,93] Very recently, however, it was discovered that the α-Syn structure changes when it is phosphorylated.…”

“…Although the etiology of synucleinopathies remains unknown, microglia were directly implicated in its pathogenesis. It is worth reiterating that microglia offer neuroprotection in the early stages of α-Syn accumulation; however, in chronic disease conditions, structural variations may accompany inherited faulty α-Syn, resulting in distorted microglial receptor interactions [ 85 , 86 ]. Thus, while microglial receptors initially enable cellular recognition and the uptake of α-Syn, in chronic disease states, the physiological functions of microglia are overwhelmed.…”

“…Thus, while microglial receptors initially enable cellular recognition and the uptake of α-Syn, in chronic disease states, the physiological functions of microglia are overwhelmed. At this stage, α-Syn processing within microglia results in neuroinflammation and neurodegeneration, which can also spread to other brain regions [ 85 , 86 ]. If microglia are overwhelmed, such as during a pathological state, their phenotype changes, and this helps the spread of α-Syn, causing disease progression [ 66 , 85 , 86 ].…”

“…At this stage, α-Syn processing within microglia results in neuroinflammation and neurodegeneration, which can also spread to other brain regions [ 85 , 86 ]. If microglia are overwhelmed, such as during a pathological state, their phenotype changes, and this helps the spread of α-Syn, causing disease progression [ 66 , 85 , 86 ]. In neurodegenerative diseases, microglial activation involves cellular metabolism dysregulation and mitochondrial damage, leading to the accumulation of reactive oxygen species (ROS), amino acids, iron, ferroptosis, and eventual inflammation and cell death [ 66 , 85 , 86 , 87 ].…”

“…If microglia are overwhelmed, such as during a pathological state, their phenotype changes, and this helps the spread of α-Syn, causing disease progression [ 66 , 85 , 86 ]. In neurodegenerative diseases, microglial activation involves cellular metabolism dysregulation and mitochondrial damage, leading to the accumulation of reactive oxygen species (ROS), amino acids, iron, ferroptosis, and eventual inflammation and cell death [ 66 , 85 , 86 , 87 ]. Recently, it was revealed that circadian rhythm also plays a critical role in microglia activation and function and that the disruption of this rhythm can lead to neurodegenerative diseases [ 88 ].…”