Extracellular Alpha-Synuclein: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Cecilia Chavarría
,
Rodrigo Ivagnes
,
José M. Souza

Alpha-synuclein (α-syn) is a small protein composed of 140 amino acids and belongs to the group of intrinsically disordered proteins. It is a soluble protein that is highly expressed in neurons and expressed at low levels in glial cells. The monomeric protein aggregation process induces the formation of oligomeric intermediates and proceeds towards fibrillar species. These α-syn conformational species have been detected in the extracellular space and mediate consequences on surrounding neurons and glial cells. In particular, higher-ordered α-syn aggregates are involved in microglial and oligodendrocyte activation, as well as in the induction of astrogliosis. These phenomena lead to mitochondrial dysfunction, reactive oxygen and nitrogen species formation, and the induction of an inflammatory response, associated with neuronal cell death. Several receptors participate in cell activation and/or in the uptake of α-syn, which can vary depending on the α-syn aggregated state and cell types. The receptors involved in this process are of outstanding relevance because they may constitute potential therapeutic targets for the treatment of PD and related synucleinopathies.

  • extracellular alpha-synuclein
  • oligomers
  • fibrils
  • astrocytes
  • oligodendrocytes
  • microglia

1. Introduction

1.1. Synucleinopathies

Parkinson’s disease (PD) is an extrapyramidal syndrome clinically characterized, as described by James Parkinson in 1817, by rigidity, tremor, and bradykinesia [1][2]. The progressive loss of dopaminergic neurons in the substantia nigra and the presence of alpha-synuclein (α-syn) protein inclusions in neuronal cell bodies, known as Lewy bodies (LBs), are the pathological hallmarks of PD [3][4][5]. The underlying pathological basis of PD remains unclear. α-Syn is the main fibrillar component of LBs in sporadic and inherited PD, and it is also part of a group of neurological diseases known as synucleinopathies, which includes multiple system atrophy (MSA), pure autonomic failure, and dementia with LBs [4][5][6][7]. It has been demonstrated that duplications and triplications of SNCA (genetic locus that encodes α-syn) are related to accelerated disease onset and progression [2][5][8][9], suggesting that increased α-syn expression is sufficient to trigger the disease process. Many animal models overexpressing wild-type or mutant forms of α-syn show cytoplasmic inclusions and motor deficits [2][5][10][11][12][13][14][15].

1.2. Alpha-Synuclein and Aggregation Process

α-Syn is a small protein composed of 140 amino acids (14 KDa) and is abundant in many regions of the brain [16][17]. α-Syn is an intrinsically disordered protein, with no defined structure. The protein has three well-characterized regions: the N-terminal region (1–60 amino acids), the hydrophobic region or non-A beta component of the Alzheimer’s disease amyloid (61–95 amino acids), and the C-terminal region (96–140 amino acids) [18][19][20][21]. The N-terminal region includes six copies of the repeat KTKEGV and is the fragment of the protein where familial mutations of the α-syn gene related to PD have been identified [22]. The hydrophobic region is the amyloidogenic part of the protein, related to the ability of α-syn to form fibrils in vitro and in vivo. This region is what distinguishes α-syn from the other members of the synuclein family [22][23][24][25][26]. The C-terminal region is rich in proline residues and has a high content of acidic amino acids, such as glutamic and aspartic acid. This contributes to the extremely low isoelectric point of α-syn (pI: 4.7) [27].
α-Syn fibril formation follows a nucleation-dependent pathway that involves many prefibrillar intermediates. The fibrillation of monomeric α-syn requires the formation of a discrete number of soluble oligomeric intermediates [28]. Oligomeric prefibrillar species include a group of intermediates of variable size and morphology [28][29][30][31][32][33][34][35][36]. Lansbury´s group has proposed that spheroidal α-syn soluble oligomers are rich in β-sheet structure and that the conversion from monomer to oligomer involves a secondary structural transition from the natively unfolded protein to predominantly β-sheets [37]. Oligomers of α-syn are formed from approximately 30 to 35 monomers and have a molecular weight of 440,000 Da. α-Syn fibrils are much larger, with about 8300 monomers per fibril and a molecular weight of around 120,000,000 Da [38]. Many reports suggest that these oligomeric species are responsible for α-syn toxicity [37][39][40][41]. It has been demonstrated that α-syn soluble oligomers disrupt membranes [37][41] and cause cell death both in vitro [30][31] and in animal models [39][40].
Therefore, processes that increase α-syn oligomer concentration, stabilize its conformation, or decrease its clearance will probably induce toxicity [35]. However, the exact role of oligomeric species in α-syn pathology is still unclear. Nevertheless, the idea that α-syn soluble oligomers are the proximal toxic species has been questioned since it has been shown that fibrils of α-syn can also induce toxicity, promote the seeding of endogenous α-syn, and may have prion-like effects [14][15][32][33][42].

2. Extracellular α-Synuclein

2.1. Putative Mechanisms of α-Syn Uptake in Cells of the Nervous System

α-Syn is a cytosolic protein that is poorly expressed in astrocytes, microglia, and oligodendrocytes [43][44]. However, it is abundantly expressed in neurons in the central nervous system (CNS). Although α-syn has no known signaling sequence, α-syn can be released from neuronal cells in small amounts via unconventional exocytosis under normal physiological conditions [45]. In pathological conditions, α-syn monomers and aggregates may be released in larger quantities and endocytosed by neighboring cells, leading to the formation of LB-like inclusions [46]. Both forms of the protein, monomeric and higher-order aggregated species, have been found in the lumen of vesicles [45].
Recent evidence showed that α-syn can propagate through neurons in the central nervous system. First, LBs were found in grafted neurons in PD patients treated with embryonic cell transplants [47][48]. Second, animal studies showed that brain inoculation of fibrillar α-syn led to the propagation of α-syn to anatomically interconnected areas of the brain, and in humans, there is evidence of trans-synaptically spreading of α-syn pathology [34][49][50][51][52]. Third, significant amounts of α-syn soluble oligomers have been detected in the plasma and cerebrospinal fluid (CSF) of patients with PD [53].

2.2. Glial Cell Uptake of Extracellular α-Syn and Activation

2.2.1. Role of Astrocytes

Astrocytes outnumber neurons in the CNS and are responsible for a wide variety of important functions, including regulation of blood flow, maintenance of the blood–brain barrier (BBB), and maintenance of the composition of the extracellular environment of ions [54]. Recent studies suggest that astrocytes play important roles in modulating neurotransmission, cell signaling, inflammation, synapse modulation, and metabolite and electrolyte homeostasis.
Damage to the CNS due to injury or disease may result in molecular, cellular, and functional changes in astrocytes, leading to ”reactive astrogliosis”. The process of astrocyte activation can be divided into three main stages or features: (i) morphological changes and cytokine production, (ii) cell proliferation, and (iii) cell migration. Some characteristics that describe reactive astrogliosis are: astrocyte hypertrophy, development of processes and cell proliferation, increased expression of the cytoskeleton glial fibrillary acidic protein (GFAP), and alterations in gene expression [54][55][56][57].
As well as other glial cells, astrocytes do not express α-syn or express it at very low levels [58]. However, the uptake of wild-type or mutant α-syn by astrocytes induces astrocyte reactivity, exhibiting neurotoxicity or inducing inflammation [59][60]. In the development of synucleinopathies, astrocytes may be activated, either by α-syn or by activated microglia [61][62]. Different α-syn aggregated forms activate glial cells to induce an inflammatory response [58][59]. Astrocytes exposed to neuron-derived α-syn aggregates underwent changes in their gene expression profiles with the induction of different proinflammatory cytokines and chemokines [63]. Reactive astrocytes can promote the release of proinflammatory cytokines and induce the production of reactive oxygen species, which will in turn affect neuronal survival and neuronal functions [59][63]. Oxidative stress has been implicated in the pathogenic mechanisms of PD and many other neurodegenerative diseases [64][65]. In response to oxidative stress, the levels of numerous cytoprotective products are increased via alteration of the Keap1 and Nrf2 system [66]. The formation of peroxynitrite and radicals derived from its homolysis leads to the oxidation and nitration of proteins [67][68][69]. In particular, for α-syn, the exposure of the protein to nitrating agents in vitro results in cross-linking and the formation of high-molecular-mass α-syn aggregates [70]. Pathological α-syn accumulation impairs the redox homeostasis in the nervous system; an increase in nuclear localization of NRF2 in post-mortem PD midbrain was detected [64].
The relevance of astrocytes in this scenario is also their participation in the clearance of neuronal α-syn, revealing an important role of astrocytes in the regulation of neuronal α-syn [71].
A relationship between mitochondrial dysfunction and α-syn has been previously reported in PD. However, most mitochondrial studies in PD were performed in neuronal cells. PD patients present an accumulation of α-syn in mitochondria and decreased complex I activity, while mice overexpressing mutated A53T α-syn have reduced complex IV activity [72][73].
Astrocytes’ cytoarchitecture dramatically changes upon exposure to oligomeric and fibrillar α-syn, with the generation of flat and polyhedral cells, retraction of the soma and nuclei, and formation of long thin processes. There is an increase in the immunostaining of the GFAP protein in astrocytes upon oligomer and fibrillar α-syn exposure along with the morphological changes. α-Syn soluble oligomers and fibrils induce the mRNA of TNF-alpha and IL-1β at similar levels to the ones obtained with LPS on astrocytes. All α-syn conformers induced the formation of reactive oxygen and nitrogen species, but only the soluble oligomeric forms led to mitochondrial dysfunction in cortical astrocytes. 

2.2.2. Role of Oligodendrocytes

Oligodendrocytes are glial cells that are responsible for the myelination of axons in the CNS, having an important role in their development, maintenance, and regeneration. Oligodendrocytes undergo a complex process of proliferation, migration, and differentiation that leads to their mature form. They also provide trophic support to neurons by releasing lactate [74][75][76][77][78]. The connection between α-syn and oligodendrocytes comes from pathology [79][80]. MSA is a progressive and severe neurodegenerative disorder that is clinically characterized by variable degrees of parkinsonism, cerebellar ataxia, and dysautonomia [81]. The hallmark of the disease is the presence of glial cytoplasmic inclusions (GCIs), which are intracellular protein aggregates, mainly composed of α-syn, located in oligodendrocytes [7][82]. Further components of GCIs are ubiquitin and other proteins, such as leucine-rich repeat serine/threonine-protein LRRK2, heat shock proteins, microtubule-associated protein tau, and prion disease-linked 14-3-3 protein, among others [82]. Analysis of single-nucleotide polymorphisms (SNPs) in the SNCA gene, the gene that encodes for α-syn, has identified an association between certain α-syn SNPs and an increased risk for the development of MSA [83].
Even though α-syn mRNAs and protein were detected in rat brain oligodendrocytes [84], α-syn expression was not detected in oligodendrocytes from healthy and MSA human brains [43]. This implies that endogenous α-syn is not enough for the formation of intracellular aggregates associated with pathology.
In response to cellular stress, oligodendrocytes suffer from oligodendroglial dysfunction. iIn a transgenic mouse model expressing α-syn in oligodendrocytes (under the control of the MBP promoter), there was a decrease in the expression of neurotrophic factors, especially glial-derived neurotrophic factor (GDNF) released from oligodendrocytes, providing new insight into the possible pathogenic mechanisms of oligodendroglial α-synucleinopathies [85].

2.2.3. Role of Microglia

Microglia are phagocytic cells of the brain that regulate brain development, the maintenance of neuronal networks, and injury repair. Accumulation and activation of microglia in the CNS have been termed microgliosis. Activated microglia change the movement of their processes from undirected to targeted towards the injured site [86]. Microglial cells express a wide range of immune receptors, such as pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) or tissue damage–associated molecular patterns (DAMPs). Microglia PRRs include toll-like receptors (TLRs), particularly TLR4 and TLR1/2 and their co-receptors [87]. 
The relationship between α-syn, microglia, and disease arises from the observation that PD patients demonstrate a marked increase in activated microglia with increased expression and concentration of proinflammatory cytokines [88][89][90]. In addition, reactive microglia assemble close to LBs in PD patients [91]. Moreover, α-syn leads to microglial activation in mouse models of protein overexpression prior to dopaminergic neuronal death [92].
Microglia exposed to α-syn soluble oligomers upregulate the expression of genes encoding TLR and the proinflammatory cytokines TNF-α and IL-1β [93]. They also present morphological changes indicative of microglial activation. Microglial activation is also associated with the generation of reactive oxygen and nitrogen species [94]. In the substantia nigra pars compacta of MSA mice, increased expression of inducible nitric oxide synthase was detected [95]. The activation of microglia and the proinflammatory response produced can accelerate the loss of dopaminergic neurons and the progression of synucleinopathies [96]. The different conformers of α-syn, mainly soluble oligomers, induce a specific response. In contrast, monomeric α-syn does not induce detectable microglial activation but promotes microglial phagocytosis [97]. α-Syn preformed fibrils (PFFs) also induced the activation of microglia [98]. Information from proteomics indicates that α-syn PFF leads to expression changes of microglial genes involved in RNA binding, mitochondrial stress, and lysosomal and autophagic functions, shedding light on the pathways involved in α-syn PFF activation of microglia [99].

2. Receptors for Extracellular α-Syn

Table 1 and Figure 1 summarize the extracellular receptors discussed here, identifying the α-syn conformer and the cell type involved. The LAG3 receptor belongs to the immunoglobulin superfamily. It is highly expressed in some immune organs, including the spleen and the thymus, and also in the central nervous system [100][101]. LAG3 can be expressed on neuronal cells and in microglia [102]. This receptor regulates T cell immune responses and immune homeostasis, mainly by inhibiting T cell activation and proliferation. LAG3 demonstrated the highest ratio of selectivity for α-syn PFF over monomeric α-syn. The internalization of α-syn PFF in neurons involves LAG3, since the deletion of LAG3 reduces the endocytosis of α-syn PFF, and this is specific for α-syn PFF. Neuron-to-neuron transmission of α-syn and the induction of neurotoxicity are attenuated by the deletion of LAG3 [103]. The lack of LAG3 delayed the α-syn PFF-induced loss of dopamine neurons, as well as biochemical and behavioral deficits in vivo [103]. Some scholars described an impairment in the pole test of animals injected with PFF, which was also prevented by LAG3 deletion [103].
/media/item_content/202206/62b9186ec83b7biomolecules-12-00655-g002.png
Figure 1. Illustration of glial cells and neurons and their interactions with different α-syn conformers, showing (a) liberation of proinflammatory cytokines from astroglial and microglial cells, contributing to their activation, (b) liberation of proinflammatory cytokines from microglial cells that affect neurons, (c) activation of astrocytes, impairing trophic support to neurons, and (d) myelination deficiency, negatively affecting axonal conduction and neuronal function.
Table 1. Glial and neuronal receptors involved in extracellular α-syn uptake in the CNS.
Receptor α-Syn Conformer Cell Type Reference
Lymphocyte-activation gene 3 (LAG3) Fibrils Neuron, microglia [102][103]
Cellular prion protein (PrPc) Fibrils, soluble oligomers Neurons [104][105]
Heparan sulfate Fibrils Neuron, oligodendrocytes [106]
Toll-like receptor 4 (TLR4) n.d. Microglia [107]
Toll-like receptor 2 (TLR2) Soluble oligomers Microglia [108]
a3-subunit of Na+/K+-ATPase Fibrils, soluble oligomers Neurons [109]
FcƔRIIB Fibrils Microglia, neurons [110]

These data suggest that extracellular α-syn fibrils can bind to LAG3 and contribute to protein-induced dopaminergic neuronal loss and neurotoxicity [103]. This receptor may play a role in α-syn spreading pathology and neurodegeneration in PD and could be considered as a therapeutic target to avoid α-syn pathology.

This entry is adapted from the peer-reviewed paper 10.3390/biom12050655

References

  1. Parkinson, J. “An essay on the shaking palsy” 200 years old. J. Neuropsychiatry Clin. Neurosci. 2002, 14, 223–236.
  2. Poewe, W.; Seppi, K.; Tanner, C.M.; Halliday, G.M.; Brundin, P.; Volkmann, J.; Schrag, A.E.; Lang, A.E. Parkinson disease. Nat. Rev. Dis. Prim. 2017, 3, 17013.
  3. Lees, A.J.; Hardy, J.; Revesz, T. Parkinson’s disease. Lancet 2009, 373, 2055–2066.
  4. Dauer, W.; Przedborski, S. Parkinson’s Disease: Mechanisms and Models. Camb. Companion Philos. Biol. 2003, 39, 889–909.
  5. Kalia, L.V.; Lang, A.E. Parkinson’s disease. Lancet 2015, 386, 896–912.
  6. Baba, M.; Nakajo, S.; Tu, P.H.; Tomita, T.; Nakaya, K.; Lee, V.M.; Trojanowski, J.Q.; Iwatsubo, T. Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am. J. Pathol. 1998, 152, 879–884.
  7. Spillantini, M.G.; Crowther, R.A.; Jakes, R.; Cairns, N.J.; Lantos, P.L.; Goedert, M. Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci. Lett. 1998, 251, 205–208.
  8. Zarranz, J.J.; Alegre, J.; Gomez-Esteban, J.C.; Lezcano, E.; Ros, R.; Ampuero, I.; Vidal, L.; Hoenicka, J.; Rodriguez, O.; Atares, B.; et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann. Neurol. 2004, 55, 164–173.
  9. Singleton, A.B.; Farrer, M.; Johnson, J.; Singleton, A.; Hague, S.; Kachergus, J.; Hulihan, M.; Peuralinna, T.; Dutra, A.; Nussbaum, R.; et al. alpha-Synuclein locus triplication causes Parkinson’s disease. Science 2003, 302, 841.
  10. Blesa, J.; Przedborski, S. Parkinson’s disease: Animal models and dopaminergic cell vulnerability. Front. Neuroanat. 2014, 8, 155.
  11. Dehay, B.; Fernagut, P.O. Alpha-synuclein-based models of Parkinson’s disease. Rev. Neurol. 2016, 172, 371–378.
  12. Duty, S.; Jenner, P. Animal models of Parkinson’s disease: A source of novel treatments and clues to the cause of the disease. Br. J. Pharmacol. 2011, 164, 1357–1391.
  13. Koprich, J.B.; Kalia, L.V.; Brotchie, J.M. Animal models of α-synucleinopathy for Parkinson disease drug development. Nat. Rev. Neurosci. 2017, 18, 515–529.
  14. Uchihara, T.; Giasson, B.I. Propagation of alpha-synuclein pathology: Hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies. Acta Neuropathol. 2016, 131, 49–73.
  15. Schaser, A.J.; Stackhouse, T.L.; Weston, L.J.; Kerstein, P.C.; Osterberg, V.R.; López, C.S.; Dickson, D.W.; Luk, K.C.; Meshul, C.K.; Woltjer, R.L.; et al. Trans-synaptic and retrograde axonal spread of Lewy pathology following pre-formed fibril injection in an in vivo A53T alpha-synuclein mouse model of synucleinopathy. Acta Neuropathol. Commun. 2020, 8, 150.
  16. Lee, V.M.; Trojanowski, J.Q. Mechanisms of Parkinson’s disease linked to pathological alpha-synuclein: New targets for drug discovery. Neuron 2006, 52, 33–38.
  17. Savitt, J.M.; Dawson, V.L.; Dawson, T.M. Diagnosis and treatment of Parkinson disease: Molecules to medicine. J. Clin. Investig. 2006, 116, 1744–1754.
  18. Chandra, S.; Chen, X.; Rizo, J.; Jahn, R.; Sudhof, T.C. A broken alpha -helix in folded alpha -Synuclein. J. Biol. Chem. 2003, 278, 15313–15318.
  19. Davidson, W.S.; Jonas, A.; Clayton, D.F.; George, J.M. Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes. J. Biol. Chem. 1998, 273, 9443–9449.
  20. George, J.M. The synucleins. Genome Biol. 2002, 3, reviews3002.1.
  21. Kahle, P.J.; Haass, C.; Kretzschmar, H.A.; Neumann, M. Structure/function of alpha-synuclein in health and disease: Rational development of animal models for Parkinson’s and related diseases. J. Neurochem. 2002, 82, 449–457.
  22. Lavedan, C. The synuclein family. Genome Res. 1998, 8, 871–880.
  23. Culvenor, J.G.; McLean, C.A.; Cutt, S.; Campbell, B.C.; Maher, F.; Jakala, P.; Hartmann, T.; Beyreuther, K.; Masters, C.L.; Li, Q.X. Non-Abeta component of Alzheimer’s disease amyloid (NAC) revisited. NAC and alpha-synuclein are not associated with Abeta amyloid. Am. J. Pathol. 1999, 155, 1173–1181.
  24. el-Agnaf, O.M.; Irvine, G.B. Aggregation and neurotoxicity of alpha-synuclein and related peptides. Biochem. Soc. Trans. 2002, 30, 559–565.
  25. Ferrer, I. Alpha-synucleinopathies. Neurologia 2001, 16, 163–170.
  26. Ueda, K.; Fukushima, H.; Masliah, E.; Xia, Y.; Iwai, A.; Yoshimoto, M.; Otero, D.A.; Kondo, J.; Ihara, Y.; Saitoh, T. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc. Natl. Acad. Sci. USA 1993, 90, 11282–11286.
  27. Hoyer, W.; Antony, T.; Cherny, D.; Heim, G.; Jovin, T.M.; Subramaniam, V. Dependence of alpha-synuclein aggregate morphology on solution conditions. J. Mol. Biol. 2002, 322, 383–393.
  28. Goedert, M.; Masuda-Suzukake, M.; Falcon, B. Like prions: The propagation of aggregated tau and α-synuclein in neurodegeneration. Brain 2017, 140, 266–278.
  29. Conway, K.A.; Harper, J.D.; Lansbury, P.T., Jr. Fibrils formed in vitro from alpha-synuclein and two mutant forms linked to Parkinson’s disease are typical amyloid. Biochemistry 2000, 39, 2552–2563.
  30. Kayed, R.; Sokolov, Y.; Edmonds, B.; McIntire, T.M.; Milton, S.C.; Hall, J.E.; Glabe, C.G. Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases. J. Biol. Chem. 2004, 279, 46363–46366.
  31. Kim, H.Y.; Cho, M.K.; Kumar, A.; Maier, E.; Siebenhaar, C.; Becker, S.; Fernandez, C.O.; Lashuel, H.A.; Benz, R.; Lange, A.; et al. Structural properties of pore-forming oligomers of alpha-synuclein. J. Am. Chem. Soc. 2009, 131, 17482–17489.
  32. Danzer, K.M.; Haasen, D.; Karow, A.R.; Moussaud, S.; Habeck, M.; Giese, A.; Kretzschmar, H.; Hengerer, B.; Kostka, M. Different species of alpha-synuclein oligomers induce calcium influx and seeding. J. Neurosci. 2007, 27, 9220–9232.
  33. Kayed, R.; Head, E.; Thompson, J.L.; McIntire, T.M.; Milton, S.C.; Cotman, C.W.; Glabe, C.G. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 2003, 300, 486–489.
  34. Volpicelli-Daley, L.A.; Luk, K.C.; Lee, V.M. Addition of exogenous alpha-synuclein preformed fibrils to primary neuronal cultures to seed recruitment of endogenous alpha-synuclein to Lewy body and Lewy neurite-like aggregates. Nat. Protoc. 2014, 9, 2135–2146.
  35. Lashuel, H.A.; Overk, C.R.; Oueslati, A.; Masliah, E. The many faces of α-synuclein: From structure and toxicity to therapeutic target. Nat. Rev. Neurosci. 2013, 14, 38–48.
  36. Alam, P.; Bousset, L.; Melki, R.; Otzen, D.E. A-Synuclein Oligomers and Fibrils: A Spectrum of Species, a Spectrum of Toxicities. J. Neurochem. 2019, 150, 522–534.
  37. Volles, M.J.; Lee, S.J.; Rochet, J.C.; Shtilerman, M.D.; Ding, T.T.; Kessler, J.C.; Lansbury, P.T., Jr. Vesicle permeabilization by protofibrillar alpha-synuclein: Implications for the pathogenesis and treatment of Parkinson’s disease. Biochemistry 2001, 40, 7812–7819.
  38. Pieri, L.; Madiona, K.; Melki, R. Structural and functional properties of prefibrillar alpha-synuclein oligomers. Sci. Rep. 2016, 6, 24526.
  39. Karpinar, D.P.; Balija, M.B.; Kugler, S.; Opazo, F.; Rezaei-Ghaleh, N.; Wender, N.; Kim, H.Y.; Taschenberger, G.; Falkenburger, B.H.; Heise, H.; et al. Pre-fibrillar alpha-synuclein variants with impaired beta-structure increase neurotoxicity in Parkinson’s disease models. EMBO J. 2009, 28, 3256–3268.
  40. Winner, B.; Jappelli, R.; Maji, S.K.; Desplats, P.A.; Boyer, L.; Aigner, S.; Hetzer, C.; Loher, T.; Vilar, M.; Campioni, S.; et al. In vivo demonstration that alpha-synuclein oligomers are toxic. Proc. Natl. Acad. Sci. USA 2011, 108, 4194–4199.
  41. Luth, E.S.; Stavrovskaya, I.G.; Bartels, T.; Kristal, B.S.; Selkoe, D.J. Soluble, prefibrillar α-synuclein oligomers promote complex I-dependent, Ca2+-induced mitochondrial dysfunction. J. Biol. Chem. 2014, 289, 21490–21507.
  42. Ferreira, N.; Gonçalves, N.P.; Jan, A.; Jensen, N.M.; Van Der Laan, A.; Mohseni, S.; Vægter, C.B.; Jensen, P.H. Trans—Synaptic spreading of alpha—Synuclein pathology through sensory afferents leads to sensory nerve degeneration and neuropathic pain. Acta Neuropathol. Commun. 2021, 9, 31.
  43. Miller, D.W.; Johnson, J.M.; Solano, S.M. Absence of a -synuclein mRNA expression in normal and multiple system atrophy oligodendroglia. J. Neural Transm. 2005, 112, 1613–1624.
  44. Booth, H.D.E.; Hirst, W.D.; Wade-Martins, R. The Role of Astrocyte Dysfunction in Parkinson’s Disease Pathogenesis. Trends Neurosci. 2017, 40, 358–370.
  45. Lee, H.-J.; Patel, S.; Lee, S.-J. Intravesicular localization and exocytosis of alpha-synuclein and its aggregates. J. Neurosci. 2005, 25, 6016–6024.
  46. Jang, A.; Lee, H.-J.; Suk, J.-E.; Jung, J.-W.; Kim, K.-P.; Lee, S.-J. Non-classical exocytosis of alpha-synuclein is sensitive to folding states and promoted under stress conditions. J. Neurochem. 2010, 113, 1263–1274.
  47. Li, J.Y.; Englund, E.; Holton, J.L.; Soulet, D.; Hagell, P.; Lees, A.J.; Lashley, T.; Quinn, N.P.; Rehncrona, S.; Bjorklund, A.; et al. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat. Med. 2008, 14, 501–503.
  48. Kordower, J.H.; Chu, Y.; Hauser, R.A.; Freeman, T.B.; Olanow, C.W. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat. Med. 2008, 14, 504–506.
  49. Surmeier, D.J.; Obeso, J.A.; Halliday, G.M. Selective neuronal vulnerability in Parkinson disease. Nat. Rev. Neurosci. 2017, 18, 101–113.
  50. Giguère, N.; Nanni, S.B.; Trudeau, L.E. On cell loss and selective vulnerability of neuronal populations in Parkinson’s disease. Front. Neurol. 2018, 9, 455.
  51. Engelender, S.; Isacson, O. The Threshold Theory for Parkinson’s Disease. Trends Neurosci. 2017, 40, 4–14.
  52. Jan, A.; Gonçalves, N.P.; Vaegter, C.B.; Jensen, P.H.; Ferreira, N. The prion-like spreading of alpha-synuclein in parkinson’s disease: Update on models and hypotheses. Int. J. Mol. Sci. 2021, 22, 8338.
  53. El-Agnaf, O.M.A.; Salem, S.A.; Paleologou, K.E.; Curran, M.D.; Gibson, M.J.; Court, J.A.; Schlossmacher, M.G.; Allsop, D. Detection of oligomeric forms of α-synuclein protein in human plasma as a potential biomarker for Parkinson’s disease. FASEB J. 2006, 20, 419–425.
  54. Sofroniew, M.V.; Vinters, H.V. Astrocytes: Biology and pathology. Acta Neuropathol. 2010, 119, 7–35.
  55. Maragakis, N.J.; Rothstein, J.D. Mechanisms of Disease: Astrocytes in neurodegenerative disease. Nat. Clin. Pract. Neurol. 2006, 2, 679–689.
  56. Pekny, M.; Pekna, M.; Messing, A.; Steinhäuser, C.; Lee, J.M.; Parpura, V.; Hol, E.M.; Sofroniew, M.V.; Verkhratsky, A. Astrocytes: A central element in neurological diseases. Acta Neuropathol. 2016, 131, 323–345.
  57. Sofroniew, M. V Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci. 2009, 32, 638–647.
  58. Tanji, K.; Imaizumi, C.A.T.; Yoshida, H.; Mori, F.; Yoshimoto, M.; Satoh, K.; Wakabayashi, K. Expression of a-synuclein in a human glioma cell line and its up-regulation by interleukin-1 beta. Neuroreport 2001, 12, 1909–1912.
  59. Chavarría, C.; Rodríguez-bottero, S.; Quijano, C.; Cassina, P.; Souza, J.M. Impact of monomeric, oligomeric and fibrillar alpha-synuclein on astrocyte reactivity and toxicity to neurons. Biochem. J. 2018, 475, 3153–3169.
  60. Roodveldt, C.; Christodoulou, J.; Dobson, C.M. Immunological features of α-synuclein in Parkinson’s disease. J. Cell. Mol. Med. 2008, 12, 1820–1829.
  61. Mavroeidi, P.; Xilouri, M. Neurons and glia interplay in α-synucleinopathies. Int. J. Mol. Sci. 2021, 22, 4994.
  62. Brück, D.; Wenning, G.K.; Stefanova, N.; Fellner, L. Glia and alpha-synuclein in neurodegeneration: A complex interaction. Neurobiol. Dis. 2016, 85, 262–274.
  63. Lee, H.J.; Kim, C.; Lee, S.J. Alpha-synuclein stimulation of astrocytes: Potential role for neuroinflammation and neuroprotection. Oxid. Med. Cell. Longev. 2010, 3, 283–287.
  64. Delaidelli, A.; Richner, M.; Jiang, L.; van der Laan, A.; Bergholdt Jul Christiansen, I.; Ferreira, N.; Nyengaard, J.R.; Vægter, C.B.; Jensen, P.H.; Mackenzie, I.R.; et al. α-Synuclein pathology in Parkinson disease activates homeostatic NRF2 anti-oxidant response. Acta Neuropathol. Commun. 2021, 9, 105.
  65. Schipper, H.M.; Liberman, A.; Stopa, E.G. Neural heme oxygenase-1 expression in idiopathic Parkinson’s disease. Exp. Neurol. 1998, 150, 60–68.
  66. Tanji, K.; Maruyama, A.; Odagiri, S.; Mori, F.; Itoh, K.; Kakita, A.; Takahashi, H.; Wakabayashi, K. Keap1 is localized in neuronal and glial cytoplasmic inclusions in various neurodegenerative diseases. J. Neuropathol. Exp. Neurol. 2013, 72, 18–28.
  67. Ferrer-sueta, G.; Campolo, N.; Trujillo, M.; Bartesaghi, S.; Carballal, S.; Romero, N.; Alvarez, B.; Radi, R. Biochemistry of Peroxynitrite and Protein Tyrosine Nitration. Chem. Rev. 2018, 118, 1338–1408.
  68. Radi, R. Nitric oxide, oxidants, and protein tyrosine nitration. Proc. Natl. Acad. Sci. USA 2004, 101, 4003–4008.
  69. Chavarría, C.; Souza, J.M. Oxidation and nitration of alpha-synuclein and their implications in neurodegenerative diseases. Arch. Biochem. Biophys. 2013, 533, 25–32.
  70. Souza, J.M.; Giasson, B.I.; Chen, Q.; Lee, V.M.Y.; Ischiropoulos, H. Dityrosine cross-linking promotes formation of stable α-synuclein polymers. Implication of nitrative and oxidative stress in the pathogenesis of neurodegenerative synucleinopathies. J. Biol. Chem. 2000, 275, 18344–18349.
  71. Tsunemi, T.; Ishiguro, Y.; Yoroisaka, A.; Valdez, C.; Miyamoto, K.; Ishikawa, K.; Saiki, S.; Akamatsu, W.; Hattori, N.; Krainc, D. Astrocytes Protect Human Dopaminergic Neurons from a -Synuclein Accumulation and Propagation. J. Neurosci. 2020, 40, 8618–8628.
  72. Martin, L.J.; Pan, Y.; Price, A.C.; Sterling, W.; Copeland, N.G.; Jenkins, N.A.; Price, D.L.; Lee, M.K. Parkinson’s disease α-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J. Neurosci. 2006, 26, 41–50.
  73. Devi, L.; Raghavendran, V.; Prabhu, B.M.; Avadhani, N.G.; Anandatheerthavarada, H.K. Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J. Biol. Chem. 2008, 283, 9089–9100.
  74. Konno, M.; Hasegawa, T.; Baba, T.; Miura, E.; Sugeno, N.; Kikuchi, A.; Fiesel, F.C.; Sasaki, T.; Aoki, M.; Itoyama, Y.; et al. Suppression of dynamin GTPase decreases -synuclein uptake by neuronal and oligodendroglial cells: A potent therapeutic target for synucleinopathy. Mol. Neurodegener. 2012, 7, 38.
  75. Reyes, J.F.; Rey, N.L.; Bousset, L.; Melki, R.; Brundin, P.; Angot, E. Alpha-synuclein transfers from neurons to oligodendrocytes. Glia 2014, 62, 387–398.
  76. Lee, Y.; Morrison, B.M.; Li, Y.; Lengacher, S.; Farah, M.H.; Hoffman, P.N.; Liu, Y.; Tsingalia, A.; Jin, L.; Zhang, P.; et al. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 2012, 487, 443–448.
  77. Funfschilling, U.; Supplie, L.M.; Mahad, D.; Boretius, S.; Aiman, S.; Edgar, J.; Brinkmann, B.G.; Kassmann, C.M.; Tzvetanova, I.D.; Sereda, W.; et al. Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 2013, 485, 517–521.
  78. Philips, T.; Rothstein, J.D. Oligodendroglia: Metabolic supporters of neurons. J. Clin. Investig. 2017, 127, 3271–3280.
  79. McCann, H.; Stevens, C.H.; Cartwright, H.; Halliday, G.M. α-Synucleinopathy phenotypes. Park. Relat. Disord. 2014, 20, S62–S67.
  80. Seidel, K.; Mahlke, J.; Siswanto, S.; Krüger, R.; Heinsen, H.; Auburger, G.; Bouzrou, M.; Grinberg, L.T.; Wicht, H.; Korf, H.W.; et al. The brainstem pathologies of Parkinson’s disease and dementia with lewy bodies. Brain Pathol. 2015, 25, 121–135.
  81. Gilman, S.; Low, P.A.; Quinn, N.; Albanese, A.; Fowler, C.J.; Kaufmann, H.; Klockgether, T.; Lang, A.E.; Lantos, P.L.; Litvan, I.; et al. Consensus statement on the diagnosis of multiple system atrophy. J. Neurol. Sci. 1999, 163, 94–98.
  82. Mccormack, A.; Chegeni, N.; Chegini, F.; Colella, A.; Power, J.; Keating, D.; Chataway, T. Purification of α-synuclein containing inclusions from human post mortem brain tissue. J. Neurosci. Methods 2016, 266, 141–150.
  83. Scholz, S.W.; Houlden, H.; Schulte, C.; Sharma, M.; Li, A.; Berg, D.; Melchers, A.; Paudel, R.; Gibbs, J.R.; Simon-Sanchez, J.; et al. SNCA variants are associated with increased risk for multiple system atrophy. Ann. Neurol. 2009, 65, 610–614.
  84. Kisos, H.; Pukaß, K.; Ben-hur, T.; Richter-landsberg, C.; Sharon, R. Increased Neuronal a -Synuclein Pathology Associates with Its Accumulation in Oligodendrocytes in Mice Modeling a -Synucleinopathies. PLoS ONE 2012, 7, e46817.
  85. Ubhi, K.; Rockenstein, E.; Mante, M.; Inglis, C.; Adame, A.; Patrick, C.; Whitney, K.; Masliah, E. Neurodegeneration in a Transgenic Mouse Model of Multiple System Atrophy Is Associated with Altered Expression of Oligodendroglial-Derived Neurotrophic Factors. J. Neurosci. 2010, 30, 6236–6246.
  86. Joers, V.; Tansey, M.; Mulas, G.; Carta, A.R. Microglial phenotypes in Parkinson’s disease and animal models of the disease. Prog. Neurobiol. 2018, 155, 57–75.
  87. Heneka, M.T.; Golenbock, D.T.; Latz, E. Innate immunity in Alzheimer’s disease. Nat. Immunol. 2015, 16, 229–236.
  88. Glanzer, J.G.; Enose, Y.; Wang, T.; Kadiu, I.; Gong, N.; Rozek, W.; Liu, J.; Schlautman, J.D.; Ciborowski, P.S.; Thomas, M.P.; et al. Genomic and proteomic microglial profiling: Pathways for neuroprotective inflammatory responses following nerve fragment clearance and activation. J. Neurochem. 2007, 102, 627–645.
  89. Biber, K.; Neumann, H.; Inoue, K.; Boddeke, H.W.G.M. Neuronal ‘ On ’ and ‘ Off ’ signals control microglia. Trends Neurosci. 2007, 30, 596–602.
  90. Mackenzie, I.R.A. Activated microglia in dementia with Lewy bodies. Neurology 2000, 55, 132–135.
  91. Ferreira, S.A.; Romero-ramos, M. Microglia Response During Parkinson’s Disease: Alpha-Synuclein Intervention. Front. Cell Neurosci. 2018, 12, 247.
  92. Theodore, S.; Shuwen Cao, B.; McLean, P.J.; Standaert, D. Targeted Overexpression of Human Alpha-Synuclein Triggers Microglial Activation and an Adaptive Immune Response in a Mouse Model of Parkinson Disease. J. Neuropathol. Exp. Neurol. 2009, 67, 1149–1158.
  93. Béraud, D.; Twomey, M.; Bloom, B.; Mittereder, A.; Ton, V.; Neitzke, K.; Chasovskikh, S.; Mhyre, T.R.; Maguire-Zeiss, K.A. α-Synuclein Alters Toll-Like Receptor Expression. Front. Neurosci. 2011, 5, 80.
  94. Hou, L.; Bao, X.; Zang, C.; Yang, H.; Sun, F.; Che, Y.; Wu, X.; Li, S.; Zhang, D.; Wang, Q. Integrin CD11b mediates α-synuclein-induced activation of NADPH oxidase through a Rho-dependent pathway. Redox Biol. 2018, 14, 600–608.
  95. Stefanova, N.; Reindl, M.; Neumann, M.; Kahle, P.J.; Poewe, W.; Wenning, G.K. Microglial Activation Mediates Neurodegeneration Related to Oligodendroglial alpha -Synucleinopathy: Implications for Multiple System Atrophy. Mov. Disord. 2007, 22, 2196–2203.
  96. Colonna, M.; Butovsky, O. Microglia Function in the Central Nervous System During Health and Neurodegeneration. Annu. Rev. Immunol. 2021, 35, 441–468.
  97. Park, J.; Paik, S.R.; Jou, I.L.O.; Park, S.M. Microglial Phagocytosis Is Enhanced by Monomeric a -Synuclein, Not Aggregated a -Synuclein: Implications for Parkinson’s Disease. Glia 2008, 1223, 1215–1223.
  98. Zhang, W.; Wang, T.; Pei, Z.; Miller, D.S.; Wu, X.; Block, M.L.; Wilson, B.; Zhang, W.; Zhou, Y.; Hong, J.-S.; et al. Aggregated -synuclein activates microglia: A process leading to disease progression in Parkinson’s disease. FASEB J. 2005, 19, 533–542.
  99. Sarkar, S.; Dammer, E.B.; Malovic, E.; Olsen, A.L.; Raza, S.A.; Gao, T.; Xiao, H.; Oliver, D.L.; Duong, D.; Joers, V.; et al. Molecular Signatures of Neuroinflammation Induced by α Synuclein Aggregates in Microglial. Front. Immunol. 2020, 11, 33.
  100. Galatro, T.F.; Holtman, I.R.; Lerario, A.M.; Vainchtein, I.D.; Brouwer, N.; Sola, P.R.; Veras, M.M.; Pereira, T.F.; Leite, R.E.P.; Möller, T.; et al. Transcriptomic analysis of purified human cortical microglia reveals age-associated changes. Nat. Neurosci. 2017, 20, 1162–1171.
  101. Zhang, Y.; Chen, K.; Sloan, S.A.; Bennett, M.L.; Scholze, A.R.; Keeffe, S.O.; Phatnani, H.P.; Guarnieri, X.P.; Caneda, C.; Ruderisch, N.; et al. An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex. J. Neurosci. 2014, 34, 11929–11947.
  102. Angelopoulou, E.; Paudel, Y.N.; Villa, C.; Shaikh, M.F.; Piperi, C. Lymphocyte-activation gene 3 (LAG3) protein as a possible therapeutic target for Parkinson’s disease: Molecular mechanisms connecting neuroinflammation to α-synuclein spreading pathology. Biology 2020, 9, 86.
  103. Mao, X.; Ou, M.T.; Karuppagounder, S.S.; Kam, T.-I.; Yin, X.; Xiong, Y.; Ge, P.; Essien Umanah, G.; Brahmachari, S.; Shin, J.-H.; et al. Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 2016, 353, aah3374.
  104. Aulić, S.; Masperone, L.; Narkiewicz, J.; Isopi, E.; Bistaffa, E.; Pastore, B.; De Cecco, E.; Scaini, D.; Zago, P.; Moda, F.; et al. α-Synuclein Amyloids Hijack Prion Protein to Gain Cell Entry, Facilitate Cell-to-Cell Spreading and Block Prion Replication. Sci. Rep. 2017, 7, 10050.
  105. Ferreira, D.G.; Temido-Ferreira, M.; Miranda, H.V.; Batalha, V.L.; Coelho, J.E.; Szegö, É.M.; Marques-Morgado, I.; Vaz, S.H.; Rhee, J.S.; Schmitz, M.; et al. α-Synuclein interacts with PrP C to induce cognitive impairment through mGluR5 and NMDAR2B. Nat. Neurosci. 2017, 20, 1569–1579.
  106. Ihse, E.; Yamakado, H.; Van Wijk, X.M.; Lawrence, R.; Esko, J.D. Cellular internalization of alpha- synuclein aggregates by cell surface heparan sulfate depends on aggregate conformation and cell type. Sci. Rep. 2017, 7, 9008.
  107. Stefanova, N.; Fellner, L.; Reindl, M.; Masliah, E.; Poewe, W.; Wenning, G.K. Toll-like receptor 4 promotes α-synuclein clearance and survival of nigral dopaminergic neurons. Am. J. Pathol. 2011, 179, 954–963.
  108. Kim, C.; Ho, D.; Suk, J.; You, S.; Michael, S.; Kang, J.; Lee, S.J.; Masliah, E.; Hwang, D.; Lee, H.; et al. Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat. Commun. 2014, 4, 1562.
  109. Shrivastava, A.N.; Redeker, V.; Fritz, N.; Pieri, L.; Almeida, L.G.; Spolidoro, M.; Liebmann, T.; Bousset, L.; Renner, M.; Léna, C.; et al. a-synuclein assemblies sequester neuronal a3-Na+/K+-ATPase and impair Na+ gradient Amulya. EMBO J. 2015, 34, 2408–2423.
  110. Choi, Y.R.; Cha, S.H.; Kang, S.J.; Kim, J.B.; Jou, I.; Park, S.M. Prion-like Propagation of α-Synuclein Is Regulated by the FcγRIIB-SHP-1/2 Signaling Pathway in Neurons. Cell Rep. 2018, 22, 136–148.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Feedback