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Review
. 2018 Nov 22:10:370.
doi: 10.3389/fnagi.2018.00370. eCollection 2018.

New Perspectives on Roles of Alpha-Synuclein in Parkinson's Disease

Guoxin Zhang  1 , Yun Xia  1 , Fang Wan  1 , Kai Ma  1 , Xingfang Guo  1 , Liang Kou  1 , Sijia Yin  1 , Chao Han  2 , Ling Liu  1 , Jinsha Huang  1 , Nian Xiong  1 , Tao Wang  1
Affiliations
Review

New Perspectives on Roles of Alpha-Synuclein in Parkinson's Disease

Guoxin Zhang et al. Front Aging Neurosci. .

Abstract

Parkinson's disease (PD) is one of the synucleinopathies spectrum of disorders typified by the presence of intraneuronal protein inclusions. It is primarily composed of misfolded and aggregated forms of alpha-synuclein (α-syn), the toxicity of which has been attributed to the transition from an α-helical conformation to a β-sheetrich structure that polymerizes to form toxic oligomers. This could spread and initiate the formation of "LB-like aggregates," by transcellular mechanisms with seeding and subsequent permissive templating. This hypothesis postulates that α-syn is a prion-like pathological agent and responsible for the progression of Parkinson's pathology. Moreover, the involvement of the inflammatory response in PD pathogenesis has been reported on the excessive microglial activation and production of pro-inflammatory cytokines. At last, we describe several treatment approaches that target the pathogenic α-syn protein, especially the oligomers, which are currently being tested in advanced animal experiments or are already in clinical trials. However, there are current challenges with therapies that target α-syn, for example, difficulties in identifying varying α-syn conformations within different individuals as well as both the cost and need of long-duration large trials.

Keywords: Parkinson’s disease; alpha-synuclein; neurodegeneration; neurotherapy; prion-like.

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Figures

FIGURE 1
FIGURE 1
(a) Native and toxic conformations of α-syn. Alpha-synuclein is able to transform into multiple different conformations, including monomers (predominant in a α-helical confirmation), tetramers, higher-level oligomers (soluble conformations), and fibrils (highly ordered insoluble conformations characterized by β-sheet conformation). Alpha-synuclein exists in a native conformation as monomers as well in a dynamic equilibrium with tetramers. The tetramer, less likely to form aggregate, must be first disrupted into monomer to further misfold. Toxic oligomers were also reported as being “on-pathway” or “off-pathway” to amyloid fibril formation. Many factors, such as the posttranscriptional modification and SNCA mutations in A53T and E46K promote to form pathological oligomers, presently considered to be the most toxic structure of α-syn, which is further folded to form amyloid fibril (rich in β-sheet structure), the accumulation of which leads to the formation of intracellular inclusions called Lewy Body. (b) Established interactions between α-syn and cellular components. The misfolded α-syn can be degraded by UPS and ALP. Certain oligomeric species present toxicity via interactions with cellular components by mechanisms that include: (1) alteration of cytoskeletal integrity; (2) membrane disruption and pore formation; (3) nuclear dysfunction; (4) inhibition of vesicle docking; (5) UPS dysfunction; (6) ALP impairment; (7) reduction of mitochondrial activity; and (8) chronic ER stress. UPS, ubiquitin-proteasomal system; ALP, autophagy-lysosomal pathway; ER, endoplasmic reticulum.
FIGURE 2
FIGURE 2
(A) Potential mechanisms involved in propagation of α-syn. Spreading mechanisms of α-syn in neighboring cells are multiple and can occur via (1) passive transmission through membrane fusion; (2) classical exocytosis and endocytosis; (3) packaged-exosomes; (4) tunneling nanotubes (a direct connection between two cells); (5) axonal transport and transsynaptic junction; and (6) receptor-mediated internalization. (B) Molecules and signaling pathways involved in α-syn-mediated microglial activation. Excessive microglial activation can increase the production of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and INF-γ), and induce an oxidative stress response, including the release of reactive oxygen species (ROS) and nitric oxide (NO) as well as the production of NADPH oxidase. Toll-like receptors (TLRs) play a vital role in recognizing pathogen-associated molecular patterns (PAMPs) and initiating innate immune responses via distinct signaling pathways, including NF-κB and MAPK activation. Activation of TLR2 resulted in the accumulation of α-syn as a result of the inhibition of autophagic activity through regulation of the AKT/mTOR pathway. Other receptors that are involved in the α-syn-induced microglial response include FcγRs/CD36/P2 × 7R/EP2/Mac-1/Ion channels. Also, α-syn induced the expression of matrix metalloproteinases (MMPs) and stimulated the activities of MAPK, NF-κB, and AP-1. In addition, MMPs may activate microglial protease-activated receptor-1 (PAR-1) in an autocrine or paracrine manner and increase microglial inflammatory signals (not shown in the diagram). Furthermore, major histocompatibility complex II (MHC-II) and Th1 cells were targeted recently for the activation of microglia. Exosomes are specifically and efficiently taken up by microglia via a macropinocytotic mechanism and are released via activation of 5-hydroxytryptamine (5-HT2a, 2b, and 5-HT4) receptors. Activated exosomes expressed a high level of MHC–II, which may be a potentially important pathway for the activation of microglia. In contrast, regulator of G-protein signaling 10 (RGS10), RING finger protein 11 (RNF11), and NF-κB essential modulator (NEMO) inhibitors exert negative regulation on NF-κB signaling, producing a dampened immune response. Finally, microglial cells are also able to phagocytose different forms of extracellular α-syn, via ubiquitin-proteasomal system (UPS) and autophagy-lysosomal pathway (ALP), presenting a mechanism of clearance that might be even beneficial for neuronal survival. The CD36 (a scavenger receptor), FcγRs (Fc gamma receptors), Mac-1 (macrophage antigen-1 receptor), EP2 (prostaglandin E2 receptor subtype 2), P2 × 7R (purinergic receptor P2×, ligand-gated ion channel 7), and plasma membrane ion channels.
FIGURE 3
FIGURE 3
Focus on toxicity of α-syn as a therapeutic target. Toxicity of alpha-synuclein to neurodegeneration is associated tightly with the dynamic equilibrium of the protein synthesis, aggregation, and clearance. Levels of specific conformations (oligomers and protofibrils) vary in different stages of PD. Disease-modifying therapeutic strategies are mainly focused on these processes as well as inhibiting cell-to-cell propagation: (i) reducing α-syn synthesis with small interfering RNA (siRNA), microRNA (miRNA), small hairpin RNA (shRNA), and transcription inhibitors; (ii) increasing degradation of α-syn via UPS and ALP; (iii) reducing aggregation of α-syn via heat-shock proteins (hsp40/70/104), aggregation inhibitors, antioxidant, and posttranslational modification approaches (oxidation, nitration, phosphorylation, and C-terminal cleavage); (iv) blocking the propagation of α-syn with immunotherapies by targeting extracellular α-syn or exosome and by blocking putative receptors in recipient cells; and (v) seeking neuroprotective strategies including anti-inflammation and antioxidant.
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