α-Synuclein in Parkinson's Disease: From Bench to Bedside

Abstract

α-Synuclein (α-syn), a pathological hallmark of PD, is emerging as a bridging element at the crossroads between neuro/immune-inflammatory responses and neurodegeneration in PD. Several evidence show that pathological α-syn accumulates in neuronal and non-neuronal cells (i.e., neurons, microglia, macrophages, skin cells, and intestinal cells) in central and peripheral tissues since the prodromal phase of the disease, contributing to brain pathology. Indeed, pathological α-syn deposition can promote neurogenic/immune-inflammatory responses that contribute to systemic and central neuroinflammation associated with PD. After providing an overview of the structure and functions of physiological α-syn as well as its pathological forms, we review current studies about the role of neuronal and non-neuronal α-syn at the crossroads between neuroinflammation and neurodegeneration in PD. In addition, we provide an overview of the correlation between the accumulation of α-syn in central and peripheral tissues and PD, related symptoms, and neuroinflammation. Special attention was paid to discussing whether targeting α-syn can represent a suitable therapeutical approach for PD.

Keywords: Parkinson's disease; central nervous system; clinical trials; gut‐brain axis; immune cells; neurodegeneration; neuroinflammation; preclinical evidence; spreading; α‐synuclein.

Figure 1

Schematic illustration of α‐synuclein pathway (a) α‐syn structure: 1. the amphipathic N‐terminal region (red), implicated in interactions with membranes. It contains the highly conserved 11‐residue repeats‐KTKEGV (yellow); 2. The hydrophobic NAC region (orange), has a major role in aggregation; 3. The negatively charged C‐terminal region (purple), regulates α‐syn interactions with other ligands. (b) In physiological status (green), α‐syn can be present through unstructured soluble monomeric and tetrameric forms. In pathological status (red), α‐syn aggregates into oligomers‐protofibrils, and fibrils, resulting in the development of Lewy Body. Abbreviations: AA, amino acids; α‐syn, α‐synunclein; T, temperature. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Schematic representation of the effects of α‐synuclein on neuronal and non‐neuronal cells. (a) Neurons: α‐syn aggregates, Lewy bodies or Lewy neurites, can promote ROS formation, alter cellular components, including proteins and DNA, and induce mitochondrial dysfunction, with consequent axonal transport disruption and synaptic dysfunction. In parallel, pathological α‐syn can trigger the polarization of astrocytes to neurotoxic A1 phenotype, leading to the release of ROS and pro‐inflammatory cytokines in the extracellular space. (b) Immune/inflammatory cells: α‐syn can be produced within immune cells that express the SNCA gene (1) or its pathological forms can be internalized from the extracellular space via endocytosis (2). Once in the intracellular space, α‐syn can seed and accumulate, forming oligomers, fibrils, and aggregates, triggering inflammatory pathways, including NLRP3 inflammasome signaling (5). Of note, both pathological and physiological forms of α‐syn can interact with TLR‐2/4 (4), promoting cellular polarization towards a pro‐inflammatory phenotype as well as the recruitment and activation of other immune/inflammatory cells (5). α‐syn can also interfere with MHC and SNARE complexes, thereby affecting antigen presentation and the trafficking of cell‐surface receptors (6, 7). (c) Physiological α‐syn in melanocytes promotes the melanin‐producing process. In keratinocytes, oligomeric α‐syn induces the release of pro‐inflammatory cytokines, such as IL‐1β and TNF. Additionally, α‐syn can be internalized by fibroblasts, leading to increased mitochondrial dysfunction, alterations in the cytoskeleton, and in turn, fibroblast cell death. Abbreviations: α‐syn, alpha‐synuclein; IL‐1β, interleukin‐1β; MHC, major histocompatibility complex; NLRP3, Nod‐like receptor protein type 3; ROS, reactive oxygen species; SNARE, soluble N‐ethylmaleimide‐sensitive‐factor attachment protein receptor; TNF, tumor necrosis factor; TLR2/4, toll‐like receptor 2 and 4. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3

Schematic representation of the interplay between α‐synuclein, neuroinflammation, and neurodegeneration in Parkinson's disease (a) Within the CNS, pathological α‐syn species are found in neuronal and non‐neuronal cells, including dopaminergic neurons in the substantia nigra, and microglial and astroglial cells, respectively, as well as in the extracellular space (1, 2, 3). The intra‐ and extracellular α‐syn promotes neuronal death (1), spreads, in a prion‐like manner, among neuronal cells (2), and induces microglial and astroglial activation (3), that, besides contributing to neurogenic/inflammatory responses, promotes the recruitment of peripheral immune/inflammatory cells (4), that further amplifying the ongoing neurodegenerative and neuroinflammatory processes. (b) The accumulation of pathological α‐syn in the ENS (1), in immune cells (2) as well as in gut barrier cells (3) can promote neurogenic/inflammatory responses, compromise further intestinal barrier integrity and permeability, and favor changes in microbiota composition (4). These events can contribute to the translocation of pathogens in the bloodstreams and α‐syn forms, including in EVs, that, in turn, can spread in the CNS via systemic circulation (5). In parallel, enteric α‐syn can spread in the brain via nerve ascending pathways (6). Both hypothesized spreading mechanisms contribute to neurodegeneration and neuroinflammation in the CNS. Abbreviations: α‐syn, alpha‐synunclein; CNS, central nervous system; ENS, enteric nervous system. [Color figure can be viewed at wileyonlinelibrary.com]