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.

Early expression of monomeric and oligomeric alpha-synuclein and tyrosine hydroxylase following intranigral injection of lipopolysaccharide

“…Although we did not observe a signi cant increase in 50 kDa oligomers, we obtained evidence of a rise in its expression. Although this increase did not reach the threshold of statistical signi cance set forth by the study, its presence is indicative of potential neurotoxicity and we consider that it is evidence that the aggregation process is happening [32][33][34].…”

Neuropathology of incidental Lewy body & prodromal Parkinson’s disease

“…Oligomers, which are small aggregates of misfolded proteins, are believed by some to be a key contributor to the neurodegenerative processes that occur in PD [ 116 ]. These oligomers are thought to be more toxic than other forms of αSyn, such as monomers or fibrils, and have been shown to impair the function of neurons in cell culture and animal models of PD.…”

Glymphatic System Pathology and Neuroinflammation as Two Risk Factors of Neurodegeneration

“…These proteins are β-amyloid (Aβ) in AD and α-synuclein (α-Syn) in PD [11]. Importantly, the role of protein aggregates in the process of neuroinflammation in the course of neurodegenerative diseases is emphasized [12,13]. Neuroinflammation, including microgliosis and astrogliosis, is closely related to neurodegenerative diseases, significantly contributing to their pathogenesis and progression [14].…”

“…As a result, proteins that originally play an essential and physiological role in the cell may gain toxicity and lose the function that drives neurodegeneration [11,60]. In PD, the protein that forms aggregates, termed Lewy bodies, is α-Syn [12]. The pathological deposition of Aβ has been observed in AD [13].…”

“…The pathological deposition of Aβ has been observed in AD [13]. The participation of these proteins in neurodegenerative processes has been emphasized in the literature [12,13]. However, the potential correlation between protein aggregates in the context of neuroinflammation and glymphatic clearance remains unclear.…”