Physiological Function of Alpha-Synuclein: Comparison
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Synucleinopathy underlies a wide spectrum of clinical syndromes, including Parkinson's disease (PD, PDD), Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and pure autonomic failure (PAF). A common feature of these syndromes is alpha-synuclein (aS) aggregation and cellular inclusions.  In synucleinopathies, the formation of the distinct αS species is determined by the nature of the self-assembly processes, which is influenced by many factors including the SNCA mutation or multiplication, epigenetic regulation, post-translational modification, micro-environments, etc.  Both the oligomeric and fibrillar forms of αS are toxic to cells.  The detrimental effects of αS continue to grow as αS fibrils start to form LBs, which can cause mitochondrial disassembly, mitophagy, mitochondrial depolarization, and synaptic dysfunction that result in progressive neurodegeneration.  

  • Alpha-Synuclein
  • Parkinson Disease
  • Lewy body
  • Neurodegeneration
  • Biomarker
  • Dementia
  • SNCA

1. Alpha-Synuclein, Lewy Body, and Dementia

Synucleinopathy underlies a wide spectrum of clinical syndromes, including PD, PDD, dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and pure autonomic failure (PAF). The first link of PD to αS was also the first conclusive demonstration of a genetic defect leading to PD, and thus has historical and conceptual value. In order to provide diagnostic accuracy and define patients likely to respond to disease -modifying therapy, a hierarchical classification has been proposed based on the underlying pathological protein deposition (αS), cellular inclusions (Lewy bodies or glial cytoplasmic inclusion, GCI), and clinical phenotypes (parkinsonism, dementia, or autonomic failure) [1]. The pathological hallmark of MSA is the presence of GCI in oligodendrocytes. In PAF, there is predominantly a peripheral deposition of Lewy bodies in autonomic ganglia and nerve fibers without evidence of central nervous system (CNS) dysfunction other than rapid eye movement sleep behavior disorder (REMSBD). Patients with PAF have an increased risk of developing PD, DLB, or MSA later in life [2], possibly indicating a pathophysiological disease continuum. REMSBD is a well-recognized prodrome of synucleinopathies [3], as well as a risk factor of developing cognitive impairment [4].
The Lewy body is a hallmark pathological feature in familial PD, sporadic PD, and other Lewy body diseases (LBD), including PDD and DLB [5][6][7]. They share αS aggregation and cellular inclusions of Lewy bodies as their key pathogenic events [8][9]. PDD and DLB are together known as Lewy body dementia, and the timing of dementia relative to the clinical features of parkinsonism is the major clinical distinction between PDD and DLB. PDD describes dementia that occurs at least one year after the onset of well-established PD (the one-year rule) [10], whereas in DLB, dementia essentially precedes or co-occurs with parkinsonism and has core features of cognitive fluctuation and visual hallucination [11]. Although PDD and DLB share many overlapping clinical and pathological features, there are major differences. Histopathologically, limbic and neocortical involvement of Lewy pathology are both found in PDD and DLB. However, there is a higher burden of neocortical and limbic LBs, more prominent cortical atrophy, and a higher prevalence of coincident Alzheimer’s disease (AD) pathology in DLB compared with PDD [12][13]. The propensity for LB propagation by seeding may differ between PDD and DLB as well [14]. On the other hand, at PDD’s early stage, it shares a similar αS pathology with PD. Clinically, DLB does not begin with PD or PDD. DLB and PDD also differ in cognitive profiles. Memory and language impairments progress faster in DLB, whereas executive dysfunction progresses more quickly in PDD [15]. Controversy still exists as to whether PDD and DLB should be considered as separate disease entities, or as two ends of the LBD spectrum beginning at the Lewy pathology end with incidental Lewy body disease, through to PD, PDD, and DLB with AD at the amyloid pathology end. There is emerging agreement in clinical trials and research settings that PDD and DLB should be distinguished as two syndromes.
Another emerging concept connecting pathophysiology and cognitive function in neurodegenerative diseases is oscillopathies, which refer to conditions characterized by the abnormal synchronization of synaptic activity [16]. Accumulation of αS can alter synaptic structure and function, in turn impairing the physiological transmission through the cortico–basal ganglia–thalamic circuits, accounting for abnormalities in motor and cognitive function. Mitochondrial dysfunction is one of the putative mechanisms in many neurodegenerative disorders. The generation of neuronal oscillations highly relies on mitochondrial energy provision. Distinct patterns of brain oscillations may correlate with clinical symptoms and network impairment secondary to physiopathological changes [17].

2. Physiological Function and Potential Toxicity of Alpha-Synuclein

Alpha-synuclein (αS) is a 140-amino-acid protein localized in presynaptic nerve terminals [18]. It has three domains with distinct biochemical properties corresponding to the amino acid composition (Figure 1). The first 60 residues are known as the N-terminal domain; this region demonstrates α-helical propensity and an amphipathic membrane binding ability [19]. The non-amyloid β-component of plaque (NAC) domain comprises residues 61–95; this region is highly amyloidogenic and responsible for protofibril and fibril formation and aggregation [20]. The carboxyl-terminal (C-terminal) domain, composed of residues 96–140, is the segment where major phosphorylation and truncation occurs. The C-terminal domain of αS limits pathologic misfolding and aggregation due to its structural factors. The negatively charged C-terminal domain works as a self-chaperone to prevent αS fibrillation by interaction with the NAC region [21]. Loss of acidic C-terminal residues through truncation promotes fibril formation [22]. The complete physiological function of αS remains unknown, though it is well established that αS is involved in various neurophysiological processes, including synaptic vesicle recycling, neurotransmission, and synaptic plasticity [23][24][25][26].
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Figure 1. The structure of the alpha-synuclein monomer. (A) Schematic depiction of alpha-synuclein structure. The amino acid residues delimiting the N-terminus, NAC region, and C-terminus as well as those that are sites of known mutations are labeled. The 140-amino-acid protein can be divided into three distinct domains. The N-terminal amphipathic domain (in blue) contains the amino acid residues affected by the main alpha-synuclein gene mutations (A30P, E46K, H50Q, G51D, A53T, A53E) associated with autosomal dominant Parkinson disease. The N-terminal region has a helical folding propensity and is responsible for membrane binding. The hydrophobic non-amyloid β-component of plaque (NAC) domain (in yellow) is responsible for promoting aggregation. The C-terminal domain (in red) forms an acidic tail containing the main phosphorylation site at Ser129. The C-terminal domain modulates alpha-synuclein aggregation. (B) Tertiary structure of the α-synuclein monomer. Created with BioRender.com (accessed on 12 October 2021).
αS is normally a soluble protein, but it can aggregate to form insoluble fibrils which, in association with other molecules such as ubiquitin, neurofilament protein, alpha B crystallin, organelles, and lipid membranes, form Lewy bodies [27][28]. αS can exist in the neuron in a monomeric, oligomeric, and soluble protofibrillary state [29]. Monomeric αS is highly dynamic and can populate a large number of different conformational or assembly states [30][31]. In synucleinopathies, the formation of the distinct αS species is determined by the nature of the self-assembly processes, which is influenced by many factors including the alpha synuclein gene (HGNC approved symbol SNCA) mutation or multiplication, epigenetic regulation, post-translational modification, micro-environments, etc. [32][33]. The distinct forms of the αS protein stack aggregates in neurons, nerve fibers, or glial cells at different rates, and can lead to mixed fibrillar polymorphs (species) with different intermolecular interactions, surface characteristics, and pathological consequences [34][35][36]. However, the precise connection between αS cluster structure and toxicity remains a subject of intense and controversial discussion [34]. We will summarize the literature in the following paragraphs. Both the oligomeric and fibrillar forms of αS are toxic to cells, but whether αS oligomers or fibrils are more toxic remains a subject of debate [34]. αS protofibrils disrupt cellular homeostasis and mediate neuronal death via intracellular targets. Secreted α-synuclein may exert deleterious effects on neighboring cells. Growing experimental evidence suggests that specific oligomeric species are the most cytotoxic forms of αS and play a key role in disease [37][38][39]. On the other hand, αS fibrils have also been reported to be toxic and their toxicity has been associated with membrane perturbation [40][41][42]. While oligomers are possibly implicated in the collapse of neuronal homeostasis, the fibrillar state(s) appears to be the most efficient at propagating itself both in vitro and in vivo. While αS oligomers possess toxic properties and are more robust than fibrils, there is no convincing evidence that they can spread in vivo rather than be formed as a collateral effect of the overall aggregation process [43]. In fact, there is no evidence that non-fibrillar oligomers can propagate in a manner similar to that of fibrils [34]. The αS fibrils can continue to aggregate in association with other proteins such as ubiquitin, neurofilament protein, and alpha B crystallin and form Lewy body-like inclusions [44][45]. The mechanistic relationship between oligomers and fibrils remains to be clarified, both in terms of oligomer assembly into fibrils and the potential dissolution of fibrils into oligomers [34]. αS clusters (oligomers and fibrils) can harm cells through various mechanisms, presumably by interacting with other biomolecules and organelles [46]. For example, it has been proposed that αS could interact with synaptic vesicles and synaptic proteins such as phospholipase D2 [47], various members of the family of RAB small GTPases [48], and SNARE complexes [35][49]. αS neurotoxicants can be classified as various channel inhibitors, receptor inhibitors, receptor agonists, synaptic vesicle inhibitors, and many more [32]. The toxicity of αS fibrils and oligomers is in part the consequence of changing the characteristics of lipid membranes. They affect, for example, membrane permeabilization and the formation of pore-like structures [50][51][52][53], lipid diffusion and packaging [54], synaptic vesicle fusion pore size [55], and membrane curvature [56]. The possible targets of αS include synaptic vesicles [57], endoplasmic reticulum (ER)–Golgi transport [58][59], mitochondria [60][61][62], and lysosomes and other proteolytic machinery [63][64][65]. The general principle is that multiple systems can be affected by αS clusters and, if they have a common attribute, they are likely to be lipid membranes [66]. The detrimental effects of αS continue to grow as αS fibrils start to form LBs. The exact mechanisms that promote the aggregation of αS into LBs and what role aggregation plays in pathogenesis remain to be clarified. A time-dependent shift in the morphology and localization of αS pathology from fibrils to cell body inclusions has been demonstrated. The initial aggregation of αS likely starts in presynaptic terminals and accumulates in axons. After reaching the neuronal cell body, αS aggregates recruit more αS monomers, undergo posttranslational modifications, and interact with other cellular components to form mature LBs. LB formation and maturation can cause mitochondrial disassembly, mitophagy, mitochondrial depolarization, and synaptic dysfunction that result in progressive neurodegeneration [44]. These findings also support the well-established concept that mitochondrial accumulation of αS is associated with impaired complex-I-dependent respiration, decreased mitochondrial membrane potential, and increased levels of reactive oxygen species [67][68]. Recent evidence supports a prion-like mechanism of αS aggregation and spread, whereby introduction of exogenous αS pre-formed fibrils causes endogenous αS to progressively adopt an insoluble, aggregated conformation [69][70]. PD patient-derived αS aggregates can also be taken up by neurons and astrocytes and induce different endogenous responses in the two cell types, leading to neuronal death [71]. However, the exact mechanism of the spreading of αS fibrils remains a subject of intense discussion. Some possible pathways may include trans-synaptic transmission, direct membrane penetration, exocytosis and endocytosis, extracellular vesicles (EVs), and tunneling nanotubes [72][73][74][75][76][77]. To sum up, the neurotoxicity of αS aggregates and LB formation can lead to (1) the disintegration of synapses [78][79][80][81], (2) mitochondrial dysfunction, (3) membrane perturbation and dysfunction [82][83][84], (4) αS-induced neuroinflammation via microglial and astrocyte activation [85], and (5) prion-like propagation between neurons. It is also worth noting that the effects of the soluble (normal) form of αS have largely been overlooked, and thus it remains unclear whether the toxicity arises from the accumulation of abnormal αS or the depletion of the soluble (normal) αS.

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