Alpha Synuclein: Neurodegeneration and Inflammation

Abstract

Alpha-Synuclein (α-Syn) is one of the most important molecules involved in the pathogenesis of Parkinson's disease and related disorders, synucleinopathies, but also in several other neurodegenerative disorders with a more elusive role. This review analyzes the activities of α-Syn, in different conformational states, monomeric, oligomeric and fibrils, in relation to neuronal dysfunction. The neuronal damage induced by α-Syn in various conformers will be analyzed in relation to its capacity to spread the intracellular aggregation seeds with a prion-like mechanism. In view of the prominent role of inflammation in virtually all neurodegenerative disorders, the activity of α-Syn will also be illustrated considering its influence on glial reactivity. We and others have described the interaction between general inflammation and cerebral dysfunctional activity of α-Syn. Differences in microglia and astrocyte activation have also been observed when in vivo the presence of α-Syn oligomers has been combined with a lasting peripheral inflammatory effect. The reactivity of microglia was amplified, while astrocytes were damaged by the double stimulus, opening new perspectives for the control of inflammation in synucleinopathies. Starting from our studies in experimental models, we extended the perspective to find useful pointers to orient future research and potential therapeutic strategies in neurodegenerative disorders.

Keywords: Disease Modifying Therapy; Parkinson’s disease; astrocytes; doxycycline; enteric nervous system; lewy body dementia; microglia; oligomeropathies; α-synuclein oligomers.

Figure 1

The pathological scenario in synucleinopathies. α-Syn in various forms, monomeric, oligomeric and fibrils, interact with neurons and glial cells. Neuronal dysfunction is induced by direct α-Syn oligomers, originating from outside or inside the cells. The permanent activation of microglial cells can induce the production of factors with detrimental effects on neuronal function, and astrocyte activation or dysfunction may contribute to neuronal damage.

Figure 2

α-Syn and neuronal dysfunction. The fibrillogenic process from monomers to Lewy bodies passes through soluble aggregates with α-Syn oligomer as an intermediate conformer. These soluble aggregates may interact directly with neuronal membrane through specific acceptor, pore formation or unspecific interference with double lipid structure. Endocytosis and exocytosis through exosomes may contribute to the formation of Lewy bodies and cell-to-cell spread of the pathology. The progress of α-Syn oligomers to protofibrils and fibrils is not inevitable, and in specific conditions, stable oligomers can be formed (oligomer off) with no further assembling.