Neurons and Glia Interplay in α-Synucleinopathies

Abstract

Accumulation of the neuronal presynaptic protein alpha-synuclein within proteinaceous inclusions represents the key histophathological hallmark of a spectrum of neurodegenerative disorders, referred to by the umbrella term a-synucleinopathies. Even though alpha-synuclein is expressed predominantly in neurons, pathological aggregates of the protein are also found in the glial cells of the brain. In Parkinson’s disease and dementia with Lewy bodies, alpha-synuclein accumulates mainly in neurons forming the Lewy bodies and Lewy neurites, whereas in multiple system atrophy, the protein aggregates mostly in the glial cytoplasmic inclusions within oligodendrocytes. In addition, astrogliosis and microgliosis are found in the synucleinopathy brains, whereas both astrocytes and microglia internalize alpha-synuclein and contribute to the spread of pathology. The mechanisms underlying the pathological accumulation of alpha-synuclein in glial cells that under physiological conditions express low to non-detectable levels of the protein are an area of intense research. Undoubtedly, the presence of aggregated alpha-synuclein can disrupt glial function in general and can contribute to neurodegeneration through numerous pathways. Herein, we summarize the current knowledge on the role of alpha-synuclein in both neurons and glia, highlighting the contribution of the neuron-glia connectome in the disease initiation and progression, which may represent potential therapeutic target for a-synucleinopathies.

Neuroglial Senescence, α-Synucleinopathy, and the Therapeutic Potential of Senolytics in Parkinson’s Disease

“…Among in vitro and in vivo models of PD, α-synuclein causes microglia to become rapidly activated, to migrate to the α-synuclein source, and then increases phagocytic and pro-inflammatory activity ( Zhang et al, 2005 ; Su et al, 2008 ; Wang et al, 2015 ; Mavroeidi and Xilouri, 2021 ). Extracellular α-synuclein is cleared through activated microglial engulfing and autophagy, mediated by TLR4-NF-kB signaling in a process recently discovered and coined as “synucleinphagy” ( Choi et al, 2020 ).…”

“…Moreover, extracellular α-synuclein can act as damaged-associated molecular patterns (DAMPs) to activate other microglial receptors and intracellular pathways, such as the Fc gamma receptor IIB (FcγRIIB) and the NF-κB pathway ( Kam et al, 2020 ). The activation of these receptors and pathways lead to reduced microglial phagocytosis, an upregulated inflammation response, α-synuclein nitration and increased release of ROS ( Zhang et al, 2007 ; Kam et al, 2020 ; Mavroeidi and Xilouri, 2021 ).…”

Is Multiple System Atrophy a Prion-like Disorder?

“…This mechanism would include the misfolding (from α-helix to β-sheet) of native proteins that aggregate into “seeds” that structurally have the capacity to corrupt proteins in their physiological conformation and induce their misfolding. Aggregated αSyn moreover can disrupt glial function, thus contributing to neurodegeneration through various pathways [ 93 ]. This process would spread in a chain reaction of misfolding and aggregation ranging from oligomers to large masses of pathologic proteins, leading to neurodegeneration, glial activation, and demyelination [ 94 , 95 ] ( Figure 1 ).…”

Mechanistic Insight from Preclinical Models of Parkinson’s Disease Could Help Redirect Clinical Trial Efforts in GDNF Therapy

“…Indeed, a diversity of pathogenic properties of the misfolded conformations and accumulating aggregates of α-syn have been associated with: (i) mitochondrial dysfunction; (ii) endoplasmic reticulum stress; (iii) proteostasis dysregulation; (iv) synaptic impairment; (v) cell apoptosis; (vi) neuroinflammation; and (vii) neurodegeneration [ 11 , 54 , 55 , 56 , 57 , 58 ].…”