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Alpha-synuclein and the prion hypothesis in Parkinson's disease
NEUROL-1959; No. of Pages 9 revue neurologique xxx (2018) xxx–xxx
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International meeting of the French society of neurology & SOFMA 2018
Alpha-synuclein and the prion hypothesis in Parkinson’s disease R. Melki * Institut Franc¸ois-Jacob, MIRCen, CEA, laboratory of Neurodegenerative Diseases, CNRS, 18, route du Panorama, 92265 Fontenay-aux-Roses cedex, France
info article
abstract
Article history:
Protein intracellular inclusions within the central nervous system are hallmarks of several
Received 29 June 2018
progressive neurodegenerative disorders in man. The protein constituents of those deposits
Received in revised form
and the affected regions within the brain differ from one neurodegenerative disorder to
2 August 2018
another. Until recently, the vicious circle consisting of spread, seeded assembly and
Accepted 21 August 2018
accumulation over time within the central nervous system of misfolded proteins aggregates
Available online xxx
was thought to be restricted to the prion protein PrP. Recent reports suggest that other
Keywords:
diseases. How alpha-synuclein protein assemblies traffic between cells, amplify by recruit-
Alpha-synuclein
ing endogenous monomeric alpha-synuclein and cause distinct synucleinopathies is
Parkinson’s disease
unclear. I review here the experimental evidence supporting the propagation of alpha-
protein aggregates spread and amplify within the central nervous system leading to distinct
Multiple system atrophy
synuclein mega-dalton assemblies in a manner similar to prion protein aggregates. I also
Dementia with Lewy bodies
describe how alpha-synuclein aggregates. I also explain why the aggregation of alpha-
prion-like propagation
synuclein may lead to distinct synucleinopathies. # 2018 Elsevier Masson SAS. All rights reserved.
1.
Alpha-synuclein and its aggregation
Misfolded protein aggregates are the hallmark of several neurodegenerative diseases in human. The main protein constituent of these aggregates and the regions within the brain that are affected differ from one neurodegenerative disorder to another. In Parkinson’s disease (PD) and related disorders, the protein alpha-synuclein forms mega-dalton assemblies named Lewy bodies and Lewy neurites after the anatomo-histo-pathologist that described them first [1,2]. The protein alpha-synuclein has multiple functions. It is involved in the maintenance of lipid-packing [3,4], in sensing
and inducing membrane curvature [5–9], in facilitating vesicle fusion [10–13] and in regulating the size of the synaptic vesicle fusion pore [14]. Upon aggregation, these functions are lost while pathologic functions are gained [15,16]. The gain of toxic function is the consequence of either:
misfolded protein aggregates-mediated permeabilization of plasma membrane and/or membranous compartments; perturbation in membrane protein dynamics and distribution; the formation of novel pathogenic signaling platforms; the trapping of significant amounts of molecular chaperones and other partner proteins within the aggregates and;
* CNRS, Neuro Psi, avenue de la Terrasse, 91190 Gif-sur-Yvette, France. E-mail address: [email protected]. https://doi.org/10.1016/j.neurol.2018.08.002 0035-3787/# 2018 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Melki R. Alpha-synuclein and the prion hypothesis in Parkinson’s disease. Revue neurologique (2018), https:// doi.org/10.1016/j.neurol.2018.08.002
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the ability of the misfolded alpha-synuclein aggregates to recruit the soluble form of the protein and amplify. Monomeric alpha-synuclein is flexible to such an extent and populates such a large ensemble of conformational states that it is considered natively unfolded [17,18]. Apha-synuclein is made of 140 amino acid residues. If we assume that each amino acid residue within alpha-synuclein can adopt a limited number of conformations, for example 3 (1 trans and 2 gauche) with 2 torsions each within the natively unfolded alphasynuclein, as the protein is made of 140 residues, the number of possible conformations alpha-synuclein could adopt would surpass 3139 2 conformations. The different conformations are in equilibrium [19]. The concentration and lifespan of each conformation are specific to each conformer and are defined by intramolecular interactions between amino acid residues stabilized by hydrogen bonds, electrostatic and hydrophobic interactions, that depend on the chemical and physical conditions surrounding the protein. Indeed, within this ensemble, the different conformations alpha-synuclein adopts, are highly dependent on the interaction of alpha-synuclein conformers with the solvent, ions, monomeric alpha-synuclein hydration, the viscosity and the pH. As the cellular environment is highly crowed, the distinct conformations alpha-synuclein adopts also depend on their differential interaction with partner molecules ranging from lipids to proteins. Thus, the nature of assembly-competent conformations alpha-synuclein populates highly depends on each given physical-chemical condition and on partner molecules in the cellular context. As for any aggregation prone protein, at any time, the probability of a monomeric alpha-synuclein molecule to populate conformers exposing amino acid stretches that allow them to establish well-defined inter-molecular interactions with molecules that are in a compatible conformation is far from negligible. As in protein crystals, interactions allowing the formation of dimers, trimers and higher molecular weight species between alpha-synuclein molecules in different conformations define the stability of the assemblies [20]. In contrast, alpha-synuclein molecules in conformations incapable of establishing stable and highly complementary interaction with the seed elongating tips cannot add on and be subsequently incorporated. As a consequence, alpha-synuclein molecules in different conformations coalesce into highly ordered structurally distinct assemblies in a stochastic manner throughout life. Point mutations (A30P, E46K, H50Q, G51D, or A53T) within SNCA, the gene encoding alpha-synuclein, duplication and triplication of this gene, increase or decrease the number of possible conformations alpha-synuclein adopts, the lifespan and concentration of these conformers. This is why, certain point mutations and gene duplication/triplication are associated with increased aggregation propensity and early onset PD [21–26]. Any given cell type has a tightly regulated and defined characteristic cellular proteostasis. When normal proteostasis is imbalanced, pathologic situations may arise. The nature of the assembly-competent conformers alpha-synuclein populates is an intrinsic characteristic of the protein, however, their lifespan and concentration is highly dependent on cellular proteostasis. Thus, while pathogenic alpha-synuclein conformers can persist in neuronal cells whose normal
proteostasis is constantly challenged by exogenous stresses such as in the olfactory bulb and the intestinal wall, such conformers are short lived in cells that are not challenged to the same extent. Molecular chaperones and the ubiquitinproteasome system (UPS) are expressed to different extents in distinct cells. They sense misfolded monomeric, low- and high-molecular-weight alpha-synuclein assemblies and constitute natural lines of cell defense. These machineries are involved in prevention of aggregation, refolding, disaggregation, and degradation of aggregation prone proteins [27]. Their efficiency was shown to decrease during aging in a cell type dependent manner. This accounts for the age – or time – dependence of synucleinopathies and other protein misfolding diseases [28]. Conditions that we define in test tubes reflect or resemble those existing within different cellular microenvironments and compartments yielding assembly-competent alpha-synuclein monomers that establish inter-molecular interactions with molecules in the same conformations, yielding stacks or high-molecular-weight assemblies [20].
2. Propagation and amplification of alphasynuclein high-molecular-weight assemblies Until recently, the spread and transmission of disease via misfolded protein aggregates was thought to be restricted to the prion protein (PrP) [29]. Evidence suggesting that aggregated PrP is not unique and that other protein aggregates that are the hallmarks of major neurodegenerative diseases propagate and amplify in a prion-like manner [30,31] came first from the work of Heiko Braak. Based on autopsy cases, Braak and co-workers noticed that pathology-associated protein aggregates initiate in circumscribed areas of the brain specific to each disease and progress in a topographically predictable manner following anatomical connections [32–35]. These observations led them to establish a disease progression scale and to hypothesize that neurotropic pathogens spread through defined pathways to interconnected regions within the central nervous system. As for PrP, these pathogens were first thought to be of viral nature. Additional evidence for the transmission of misfolded protein aggregates not involving PrP in man came from the observation that Lewy bodies in PD brains contaminate grafted fetal mesencephalic progenitor neurons decades after transplantation [36,37]. These observations prompted several teams to inject brain homogenates from model animals that develop early disease onset and from patients developing distinct synucleinopathies, fractionated or not, into the central nervous system (CNS) of naı¨ve model animals ranging from rodents to non-human primates and to demonstrate that they induce the appearance of lesions reminiscent of synucleinopathies in their CNS [38– 45]. No such lesions were observed with equivalent control samples lacking the characteristic mega-dalton alphasynuclein assemblies. The lesions, initially confined to the injected brain region, propagated to neighboring and/or axonally connected areas over several months, suggesting directed spreading and amplification through neuronal transport processes. Beside triggering the aggregation of
Please cite this article in press as: Melki R. Alpha-synuclein and the prion hypothesis in Parkinson’s disease. Revue neurologique (2018), https:// doi.org/10.1016/j.neurol.2018.08.002
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the monomeric form of the protein in cell culture [46–51], alpha-synuclein high-molecular-weight assemblies made de novo from recombinant protein induced similar lesions and triggered the aggregation of endogenous alpha-synuclein several months after injection into the CNS [51–55]. They were also transported to the CNS after peripheral delivery into the intestinal wall, the blood stream or the skeletal muscles [55–57]. Finally, the experimental evidence that reproduced the best the seminal observation that Lewy bodies in PD brains contaminate grafted fetal mesencephalic progenitor neurons decades after transplantation came from the compelling observation that Lewy bodies of human nature appeared over time in rodent neural grafts implanted in the brains of mice expressing human alpha-synuclein [49,58,59]. Altogether, these observations strongly support the notion that in vivo or in vitro aggregated alpha-synuclein propagates and amplifies in a prion-like manner.
3. Structural-molecular basis of distinct synucleinopathies As for the prion protein PrP, whose de novo or contaminationmediated aggregation in given organisms yields distinct diseases with characteristic incubation times, brain lesions and proteolytic cleavage patterns, e.g. classical or Nor98 scrapie in sheep, classical or atypical bovine spongiform encephalopathies (H-BSE and L-BSE) in bovines and different neurodegenerative diseases in humans (CJD, new variant CJD, kuru, FFI, GSS) [29,60], alpha-synuclein aggregation yields PD, DLD, ILDB and MSA in humans. Fractionated brain homogenates from MSA or PD cases have been reported to faithfully induce lesions characteristic of each synucleinopathy upon injection in the CNS of model rodents and/or non-human primates [40–45]. Alpha-synuclein fibrillar assemblies generated under different experimental conditions were shown to yield PD or MSA pathological hallmarks in rodents [55]. How the aggregation of one given protein can yield distinct diseases is a central question not only for a better understanding of the structural-molecular determinants of different diseases but also the design of therapeutic interventions aimed at inhibiting disease occurrence and progression. As stated above, monomeric alpha-synuclein populates a very large ensemble of conformational states. This is schematized in Fig. 1. Within this ensemble, several assembly-competent alpha-synuclein monomers may co-exist with assembly-incompetent monomers and coalesce into distinct fibrils (labeled red and blue in Fig. 1). The assembly-competent conformation alpha-synuclein monomers populates are rich in beta-strands (Fig. 2). They fold in space into different conformations and expose distinct polypeptide chains that define different sets of inter-molecular interactions with molecules in the same conformations (Fig. 2). This yields alpha-synuclein molecules stacks or assemblies that possess different intrinsic architectures e.g. structural characteristics (Fig. 2). Moreover, alpha-synuclein monomers in different conformations within pathogenic assemblies expose distinct amino acid stretches at their surfaces. Thus, the different tertiary structures monomeric alpha-synuclein adopts (Fig. 2)
Fig. 1 – Alpha-synuclein aggregation into distinct highmolecular-weight polymorphs. Alpha-synuclein adopts multiple conformations. Some conformations are capable of interacting with molecules in the same conformation. To schematize, monomeric alpha-synuclein molecules with hexagonal or rectangular shapes will establish thermodynamically stable inter-molecular interactions with an assembly made of bricks with hexagonal or rectangular shapes, respectively. The inter-molecular interactions a monomeric alpha-synuclein molecule with hexagonal shape establishes upon docking to an assembly made of bricks with rectangular shapes, and vice versa, are unstable as they do not outweigh the entropic cost of binding. The faithful maintenance of the intrinsic structure of the seeds is dictated by the establishment of structurally well-defined and highly specific longitudinal and lateral interactions the seeds ends establish with newly recruited, conformationally compatible alpha-synuclein molecules.
dictate both the inter-molecular interactions and the surface characteristics of different assembly polymorphs (Fig. 2). The surfaces of structurally distinct assemblies that are exposed to solvent rule their ability to:
grow by incorporating monomeric alpha-synuclein molecules in conformations that can establish thermodynamically stable interactions with assembly tips; stack laterally into bundles; interact with partner proteins at the surface of the cell or within the cytosol and phospholipids and 4 – be posttranslationally modified and/or processed by the UPS. As a
Please cite this article in press as: Melki R. Alpha-synuclein and the prion hypothesis in Parkinson’s disease. Revue neurologique (2018), https:// doi.org/10.1016/j.neurol.2018.08.002
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Fig. 2 – Prion-like propagation of pathogenic alpha-synuclein assemblies. Pathogenic alpha-synuclein assemblies (red star and electron micrograph) are released from dying neurons (left). They are taken up by naı¨ve neurons, astrocytes, oligodendrocytes, etc. . . The assemblies can also be released by affected neurons either naked or within membranous particles (exosomes and ectosomes). After binding to protein partners at the surface of naı¨ve cells, the assemblies are taken up by either endocytosis/micropinocytosis or through unconventional processes. The assemblies also traffic between affected and naı¨ve cells through cell contacts (e.g. synapses) or membranous structures (tunneling nanotubes). The assemblies have been shown to rupture the endo-lysosomal membranous compartment and to reach the cytosol of naı¨ve cells where they can grow and amplify by recruitment of monomeric alpha-synuclein.
result, they dictate the functional properties of alphasynuclein assemblies such as their seeding propensity, resistance to the cellular clearance machinery, tropism for different neuronal cells, toxicity, etc. . . The secondary structure content of different alphasynuclein fibrillar polymorphs generated by various laboratories under different experimental conditions and/or from Cterminally truncated forms of alpha-synuclein have been determined [61–66]. Comparison of the different structural features [65] reveals the capacity of full-length or C-terminally truncated alpha-synuclein to populate different conformers that possess assembly propensity that yield structurally and functionally distinct fibrillar assemblies. The chameleon properties of alpha-synuclein is illustrated by the two most accomplished structures that have been published [67,68]. Indeed, the latter differ not only by the number of protofilaments constituting the fibrils, 1 versus 2, but also by the fold alpha-synuclein adopts within the fibrillar structures (Fig. 2).
4. Relationship between alpha-synuclein strains and different synucleinopathies The amino acid stretches exposed at the surfaces of structurally distinct alpha-synuclein assemblies define their different interactomes. This spans from tropism to different neuronal cell populations when they are outside the cells to different
organelles and proteins when they are within the cytosol. Alpha-synuclein assemblies have been shown to interact with defined sets of extracellular matrix components (e.g. HSPGs and agrin), lipids (cholesterol and the gangliosides GM1 and GM3) and membrane proteins (ranging from lymphocyte activation gene 3, neurexin-subunits, amyloid b precursor-like protein 1, a3-Na+/K+-ATPase to 78 kDa glucose-related protein) exposed at the surface of neuronal cells [69–71]. The presence of these proteins and their abundance on the surface of neuronal cells define the tropism of distinct pathogenic alpha-synuclein assemblies toward defined cell populations within the CNS or to defined membranous structures (e.g. lipid rafts). The tropism of structurally distinct preformed fibrillar polymorphs for different neuronal cells is illustrated by the observation made in vivo that different a-synuclein strains target preferentially neurons or oligodendrocytes triggering Lewy body and neurite formation in neurons and/or yielding inclusions characteristic of multiple system atrophy in oligodendrocytes [55]. A time-dependent clustering of alpha-synuclein assemblies was reported after their diffusion within the cell membrane and interaction with their partners at the plasma membrane. The preferential clustering of alpha-synuclein assemblies around curved membranous structures such as synapses could be either due to their higher affinity for defined membrane geometry [8] or to partner molecules enriched within these structures. This affects the dynamic properties of partner molecules and membrane geometry which in turn favors both the redistribution of these partners and that of
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associated proteins, leading through a snowball effect to aberrant, non-physiological distribution and, eventually, pathological gain or loss of signaling functions [72]. After binding, structurally distinct alpha-synuclein assemblies are taken up mostly through endocytosis [73]. They are directed towards the lysosomal compartment. A fraction appears to escape during membrane fusion events and/or lysosomal membrane disruption [74,75]. This fraction highly depends on distinct alpha-synuclein assemblies exposing different polypeptide chains at their surfaces for their ability to resist the clearance machinery within the lysosomes. Within the cytosol, distinct alpha-synuclein assembly polymorphs interact with diverse protein partners in a manner dependent on their surfaces. Such interactions are expected to imbalance proteostasis to different extents following the titration of cytosolic molecular chaperones and/or saturation of the cell’s clearance machinery [76,77]. Other partner proteins may also get trapped in non-functional states. Furthermore, distinct alpha-synuclein polymorphs grow and amplify till exhaustion of their functional cytosolic form in a manner dependent on the extent to which the specific alpha-synuclein conformers they recruit are populated and on their recruitment efficiency [48,50]. Finally, within the cytosol, exogenous or amplified alphasynuclein polymorphs certainly interact with the mitochondrial, Golgi and endoplasmic reticulum membranes to different degrees, leading to organelle dysfunctions [78–83]. An additional factor that defines the type of synucleinopathy may be the degree of co-existence of alpha-synuclein and other pathogenic protein inclusions, in particular tau inclusions. Indeed, a wide range of synucleinopathies such as PD
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with dementia (PDD), DLB, Lewy body variant of Alzheimer’s disease (LBVAD), Guam-Parkinson-ALS dementia complex or Down’s syndrome and more than 50% of Alzheimer disease cases are characterized by the co-occurrence of alphasynuclein and tau inclusions, suggesting that there is a considerable crosstalk between these diseases [84,85]. This suggests that the co-existence of alpha-synuclein and tau inclusions as ‘‘teammates in neurodegeneration’’ [76] is the rule and not the exception and underlines the impact of proteostasis imbalance in distinct synucleinopathies. The amino acid stretches exposed at distinct alphasynuclein assembly extremities dictate their ability to grow and their interactomes, respectively. The ends of alphasynuclein high-molecular-weight polymorphs define the rate at which they elongate by recruitment of alpha-synuclein molecules in conformations that can establish highly complementary interactions. The rate at which functional alphasynuclein is exhausted in cells after aggregation contributes to disease phenotype. Thus, by recruiting their soluble alphasynuclein and depleting the cells from the functional form of the protein with different efficiencies, pathogenic alphasynuclein seeds define the speed at which synucleinopathies evolve as a function of time/age. The sides of pathogenic alpha-synuclein assemblies play a central role in disease [86] as they modulate:
their capacity to interact laterally to form bundles through hydrophobic or electrostatic interactions or via interaction with bridging cellular proteins;
Fig. 3 – The different fibrillar polymorphs alpha-synuclein conformations dictate. Natively unfolded alpha-synuclein (A), adopts a beta-strand-rich conformation (B), that can fold in space into different theoretical tertiary structures (C). One such conformation derived from solid-state NMR measurements is shown (D). Te molecules establish inter-molecular hydrogen bonds allowing them to pile up to constitute the fibrillar core (E, top and side views). One such fibrillar scaffold derived from solid-state NMR measurements [67] is shown (F). Dynamic N- and C-terminal amino acid stretches may project from the amyloid fibrillar core (F). A recent fibrillar structure, obtained by cryo-electron microscopy [68] reveals not only that the fibrillar core is constituted by two back-to back protofilaments (G) as opposed to one (F) but also an alpha-synuclein fold different from that derived from solid-state NMR measurements [67].
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their ability to form macromolecular structures within neuronal cells; their resistance to degradation and the cellular clearance machinery; their ability to be post-translationally modified or not; their interaction with partner proteins within the membrane and the cytosol and the redistribution of the latter; the rate at which they escape from the endo-lysosomal compartment after their uptake from the extracellular milieu; their capacity to interact with different cargos and molecular motors and to be transported anterogradely and retrogradely within neurons and; their ability to traffic/propagate from cell to cell through tunneling nanotubes [87–89], through synapses [53] or upon active export and import (exo- and endocytosis) [90,91] (Fig. 3). Besides determining the ability of pathologic protein assemblies to associate laterally and clearance propensity, depending on whether they expose proteolytic cleavage sites or not, the amino acid stretches exposed on the sides of pathologic protein assemblies define their interactomes. The full interactomes of pathogenic protein aggregates whether in the cytoplasm or at the plasma membrane is far from being fully identified. Nonetheless, it is reasonable to consider that different polymorphs are capable of interacting with overlapping but distinct partner protein ensembles and that the interactions lead to a redistribution of these partners, their possible loss of function upon the formation of different alpha-synuclein polymorph-partner protein complexes, and subsequent pathologies. The consequence of differential growth rates, bundling and resistance to degradation of exogenous alpha-synuclein strains has been assessed in vitro and in vivo. Different fulllength alpha-synuclein strains, seeded reporter alpha-synuclein aggregation in cultured cells, and aggregate persistence over generations after single exposure to the strains vary to very different extents [48]. Distinct strains were found to trigger aggregation of endogenous alpha-synuclein within rodents to different extents and imprinted their intrinsic structural characteristics [55]. Altogether these observations suggest that different strains exhibit different tropisms to cell populations within the CNS through the surfaces they expose and partners they interact with. This can lead to different distributions and phenotypes in distinct synucleinopathies.
Disclosure of interest The author declares that he has no competing interest.
Acknowledgements Research carried out in RM laboratory is sponsored by the Centre National de la Recherche Scientifique and grants from the Agence Nationale de la Recherche Scientifique, European
Commission Joint Programme on Neurodegenerative Diseases (JPND-Synaction JPND-TransPathND and JPND- PROTEST-70), Innovative Medicine Initiative 2 Joint grant agreement No 116060 (IMPRiND, www.imprind.org) supported by the European Union’s Horizon 2020 research and innovation program and EFPIA, the Institut de France-Fondation Simone et Cino Del Duca, the Fondation Bettencourt Schueller, the Fondation Pour La Recherche Me´dicale contract DEQ20160334896 and the Fondation de France.
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Available online at
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International meeting of the French society of neurology & SOFMA 2018
Alpha-synuclein and the prion hypothesis in Parkinson’s disease R. Melki * Institut Franc¸ois-Jacob, MIRCen, CEA, laboratory of Neurodegenerative Diseases, CNRS, 18, route du Panorama, 92265 Fontenay-aux-Roses cedex, France
info article
abstract
Article history:
Protein intracellular inclusions within the central nervous system are hallmarks of several
Received 29 June 2018
progressive neurodegenerative disorders in man. The protein constituents of those deposits
Received in revised form
and the affected regions within the brain differ from one neurodegenerative disorder to
2 August 2018
another. Until recently, the vicious circle consisting of spread, seeded assembly and
Accepted 21 August 2018
accumulation over time within the central nervous system of misfolded proteins aggregates
Available online xxx
was thought to be restricted to the prion protein PrP. Recent reports suggest that other
Keywords:
diseases. How alpha-synuclein protein assemblies traffic between cells, amplify by recruit-
Alpha-synuclein
ing endogenous monomeric alpha-synuclein and cause distinct synucleinopathies is
Parkinson’s disease
unclear. I review here the experimental evidence supporting the propagation of alpha-
protein aggregates spread and amplify within the central nervous system leading to distinct
Multiple system atrophy
synuclein mega-dalton assemblies in a manner similar to prion protein aggregates. I also
Dementia with Lewy bodies
describe how alpha-synuclein aggregates. I also explain why the aggregation of alpha-
prion-like propagation
synuclein may lead to distinct synucleinopathies. # 2018 Elsevier Masson SAS. All rights reserved.
1.
Alpha-synuclein and its aggregation
Misfolded protein aggregates are the hallmark of several neurodegenerative diseases in human. The main protein constituent of these aggregates and the regions within the brain that are affected differ from one neurodegenerative disorder to another. In Parkinson’s disease (PD) and related disorders, the protein alpha-synuclein forms mega-dalton assemblies named Lewy bodies and Lewy neurites after the anatomo-histo-pathologist that described them first [1,2]. The protein alpha-synuclein has multiple functions. It is involved in the maintenance of lipid-packing [3,4], in sensing
and inducing membrane curvature [5–9], in facilitating vesicle fusion [10–13] and in regulating the size of the synaptic vesicle fusion pore [14]. Upon aggregation, these functions are lost while pathologic functions are gained [15,16]. The gain of toxic function is the consequence of either:
misfolded protein aggregates-mediated permeabilization of plasma membrane and/or membranous compartments; perturbation in membrane protein dynamics and distribution; the formation of novel pathogenic signaling platforms; the trapping of significant amounts of molecular chaperones and other partner proteins within the aggregates and;
* CNRS, Neuro Psi, avenue de la Terrasse, 91190 Gif-sur-Yvette, France. E-mail address: [email protected]. https://doi.org/10.1016/j.neurol.2018.08.002 0035-3787/# 2018 Elsevier Masson SAS. All rights reserved.
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the ability of the misfolded alpha-synuclein aggregates to recruit the soluble form of the protein and amplify. Monomeric alpha-synuclein is flexible to such an extent and populates such a large ensemble of conformational states that it is considered natively unfolded [17,18]. Apha-synuclein is made of 140 amino acid residues. If we assume that each amino acid residue within alpha-synuclein can adopt a limited number of conformations, for example 3 (1 trans and 2 gauche) with 2 torsions each within the natively unfolded alphasynuclein, as the protein is made of 140 residues, the number of possible conformations alpha-synuclein could adopt would surpass 3139 2 conformations. The different conformations are in equilibrium [19]. The concentration and lifespan of each conformation are specific to each conformer and are defined by intramolecular interactions between amino acid residues stabilized by hydrogen bonds, electrostatic and hydrophobic interactions, that depend on the chemical and physical conditions surrounding the protein. Indeed, within this ensemble, the different conformations alpha-synuclein adopts, are highly dependent on the interaction of alpha-synuclein conformers with the solvent, ions, monomeric alpha-synuclein hydration, the viscosity and the pH. As the cellular environment is highly crowed, the distinct conformations alpha-synuclein adopts also depend on their differential interaction with partner molecules ranging from lipids to proteins. Thus, the nature of assembly-competent conformations alpha-synuclein populates highly depends on each given physical-chemical condition and on partner molecules in the cellular context. As for any aggregation prone protein, at any time, the probability of a monomeric alpha-synuclein molecule to populate conformers exposing amino acid stretches that allow them to establish well-defined inter-molecular interactions with molecules that are in a compatible conformation is far from negligible. As in protein crystals, interactions allowing the formation of dimers, trimers and higher molecular weight species between alpha-synuclein molecules in different conformations define the stability of the assemblies [20]. In contrast, alpha-synuclein molecules in conformations incapable of establishing stable and highly complementary interaction with the seed elongating tips cannot add on and be subsequently incorporated. As a consequence, alpha-synuclein molecules in different conformations coalesce into highly ordered structurally distinct assemblies in a stochastic manner throughout life. Point mutations (A30P, E46K, H50Q, G51D, or A53T) within SNCA, the gene encoding alpha-synuclein, duplication and triplication of this gene, increase or decrease the number of possible conformations alpha-synuclein adopts, the lifespan and concentration of these conformers. This is why, certain point mutations and gene duplication/triplication are associated with increased aggregation propensity and early onset PD [21–26]. Any given cell type has a tightly regulated and defined characteristic cellular proteostasis. When normal proteostasis is imbalanced, pathologic situations may arise. The nature of the assembly-competent conformers alpha-synuclein populates is an intrinsic characteristic of the protein, however, their lifespan and concentration is highly dependent on cellular proteostasis. Thus, while pathogenic alpha-synuclein conformers can persist in neuronal cells whose normal
proteostasis is constantly challenged by exogenous stresses such as in the olfactory bulb and the intestinal wall, such conformers are short lived in cells that are not challenged to the same extent. Molecular chaperones and the ubiquitinproteasome system (UPS) are expressed to different extents in distinct cells. They sense misfolded monomeric, low- and high-molecular-weight alpha-synuclein assemblies and constitute natural lines of cell defense. These machineries are involved in prevention of aggregation, refolding, disaggregation, and degradation of aggregation prone proteins [27]. Their efficiency was shown to decrease during aging in a cell type dependent manner. This accounts for the age – or time – dependence of synucleinopathies and other protein misfolding diseases [28]. Conditions that we define in test tubes reflect or resemble those existing within different cellular microenvironments and compartments yielding assembly-competent alpha-synuclein monomers that establish inter-molecular interactions with molecules in the same conformations, yielding stacks or high-molecular-weight assemblies [20].
2. Propagation and amplification of alphasynuclein high-molecular-weight assemblies Until recently, the spread and transmission of disease via misfolded protein aggregates was thought to be restricted to the prion protein (PrP) [29]. Evidence suggesting that aggregated PrP is not unique and that other protein aggregates that are the hallmarks of major neurodegenerative diseases propagate and amplify in a prion-like manner [30,31] came first from the work of Heiko Braak. Based on autopsy cases, Braak and co-workers noticed that pathology-associated protein aggregates initiate in circumscribed areas of the brain specific to each disease and progress in a topographically predictable manner following anatomical connections [32–35]. These observations led them to establish a disease progression scale and to hypothesize that neurotropic pathogens spread through defined pathways to interconnected regions within the central nervous system. As for PrP, these pathogens were first thought to be of viral nature. Additional evidence for the transmission of misfolded protein aggregates not involving PrP in man came from the observation that Lewy bodies in PD brains contaminate grafted fetal mesencephalic progenitor neurons decades after transplantation [36,37]. These observations prompted several teams to inject brain homogenates from model animals that develop early disease onset and from patients developing distinct synucleinopathies, fractionated or not, into the central nervous system (CNS) of naı¨ve model animals ranging from rodents to non-human primates and to demonstrate that they induce the appearance of lesions reminiscent of synucleinopathies in their CNS [38– 45]. No such lesions were observed with equivalent control samples lacking the characteristic mega-dalton alphasynuclein assemblies. The lesions, initially confined to the injected brain region, propagated to neighboring and/or axonally connected areas over several months, suggesting directed spreading and amplification through neuronal transport processes. Beside triggering the aggregation of
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the monomeric form of the protein in cell culture [46–51], alpha-synuclein high-molecular-weight assemblies made de novo from recombinant protein induced similar lesions and triggered the aggregation of endogenous alpha-synuclein several months after injection into the CNS [51–55]. They were also transported to the CNS after peripheral delivery into the intestinal wall, the blood stream or the skeletal muscles [55–57]. Finally, the experimental evidence that reproduced the best the seminal observation that Lewy bodies in PD brains contaminate grafted fetal mesencephalic progenitor neurons decades after transplantation came from the compelling observation that Lewy bodies of human nature appeared over time in rodent neural grafts implanted in the brains of mice expressing human alpha-synuclein [49,58,59]. Altogether, these observations strongly support the notion that in vivo or in vitro aggregated alpha-synuclein propagates and amplifies in a prion-like manner.
3. Structural-molecular basis of distinct synucleinopathies As for the prion protein PrP, whose de novo or contaminationmediated aggregation in given organisms yields distinct diseases with characteristic incubation times, brain lesions and proteolytic cleavage patterns, e.g. classical or Nor98 scrapie in sheep, classical or atypical bovine spongiform encephalopathies (H-BSE and L-BSE) in bovines and different neurodegenerative diseases in humans (CJD, new variant CJD, kuru, FFI, GSS) [29,60], alpha-synuclein aggregation yields PD, DLD, ILDB and MSA in humans. Fractionated brain homogenates from MSA or PD cases have been reported to faithfully induce lesions characteristic of each synucleinopathy upon injection in the CNS of model rodents and/or non-human primates [40–45]. Alpha-synuclein fibrillar assemblies generated under different experimental conditions were shown to yield PD or MSA pathological hallmarks in rodents [55]. How the aggregation of one given protein can yield distinct diseases is a central question not only for a better understanding of the structural-molecular determinants of different diseases but also the design of therapeutic interventions aimed at inhibiting disease occurrence and progression. As stated above, monomeric alpha-synuclein populates a very large ensemble of conformational states. This is schematized in Fig. 1. Within this ensemble, several assembly-competent alpha-synuclein monomers may co-exist with assembly-incompetent monomers and coalesce into distinct fibrils (labeled red and blue in Fig. 1). The assembly-competent conformation alpha-synuclein monomers populates are rich in beta-strands (Fig. 2). They fold in space into different conformations and expose distinct polypeptide chains that define different sets of inter-molecular interactions with molecules in the same conformations (Fig. 2). This yields alpha-synuclein molecules stacks or assemblies that possess different intrinsic architectures e.g. structural characteristics (Fig. 2). Moreover, alpha-synuclein monomers in different conformations within pathogenic assemblies expose distinct amino acid stretches at their surfaces. Thus, the different tertiary structures monomeric alpha-synuclein adopts (Fig. 2)
Fig. 1 – Alpha-synuclein aggregation into distinct highmolecular-weight polymorphs. Alpha-synuclein adopts multiple conformations. Some conformations are capable of interacting with molecules in the same conformation. To schematize, monomeric alpha-synuclein molecules with hexagonal or rectangular shapes will establish thermodynamically stable inter-molecular interactions with an assembly made of bricks with hexagonal or rectangular shapes, respectively. The inter-molecular interactions a monomeric alpha-synuclein molecule with hexagonal shape establishes upon docking to an assembly made of bricks with rectangular shapes, and vice versa, are unstable as they do not outweigh the entropic cost of binding. The faithful maintenance of the intrinsic structure of the seeds is dictated by the establishment of structurally well-defined and highly specific longitudinal and lateral interactions the seeds ends establish with newly recruited, conformationally compatible alpha-synuclein molecules.
dictate both the inter-molecular interactions and the surface characteristics of different assembly polymorphs (Fig. 2). The surfaces of structurally distinct assemblies that are exposed to solvent rule their ability to:
grow by incorporating monomeric alpha-synuclein molecules in conformations that can establish thermodynamically stable interactions with assembly tips; stack laterally into bundles; interact with partner proteins at the surface of the cell or within the cytosol and phospholipids and 4 – be posttranslationally modified and/or processed by the UPS. As a
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Fig. 2 – Prion-like propagation of pathogenic alpha-synuclein assemblies. Pathogenic alpha-synuclein assemblies (red star and electron micrograph) are released from dying neurons (left). They are taken up by naı¨ve neurons, astrocytes, oligodendrocytes, etc. . . The assemblies can also be released by affected neurons either naked or within membranous particles (exosomes and ectosomes). After binding to protein partners at the surface of naı¨ve cells, the assemblies are taken up by either endocytosis/micropinocytosis or through unconventional processes. The assemblies also traffic between affected and naı¨ve cells through cell contacts (e.g. synapses) or membranous structures (tunneling nanotubes). The assemblies have been shown to rupture the endo-lysosomal membranous compartment and to reach the cytosol of naı¨ve cells where they can grow and amplify by recruitment of monomeric alpha-synuclein.
result, they dictate the functional properties of alphasynuclein assemblies such as their seeding propensity, resistance to the cellular clearance machinery, tropism for different neuronal cells, toxicity, etc. . . The secondary structure content of different alphasynuclein fibrillar polymorphs generated by various laboratories under different experimental conditions and/or from Cterminally truncated forms of alpha-synuclein have been determined [61–66]. Comparison of the different structural features [65] reveals the capacity of full-length or C-terminally truncated alpha-synuclein to populate different conformers that possess assembly propensity that yield structurally and functionally distinct fibrillar assemblies. The chameleon properties of alpha-synuclein is illustrated by the two most accomplished structures that have been published [67,68]. Indeed, the latter differ not only by the number of protofilaments constituting the fibrils, 1 versus 2, but also by the fold alpha-synuclein adopts within the fibrillar structures (Fig. 2).
4. Relationship between alpha-synuclein strains and different synucleinopathies The amino acid stretches exposed at the surfaces of structurally distinct alpha-synuclein assemblies define their different interactomes. This spans from tropism to different neuronal cell populations when they are outside the cells to different
organelles and proteins when they are within the cytosol. Alpha-synuclein assemblies have been shown to interact with defined sets of extracellular matrix components (e.g. HSPGs and agrin), lipids (cholesterol and the gangliosides GM1 and GM3) and membrane proteins (ranging from lymphocyte activation gene 3, neurexin-subunits, amyloid b precursor-like protein 1, a3-Na+/K+-ATPase to 78 kDa glucose-related protein) exposed at the surface of neuronal cells [69–71]. The presence of these proteins and their abundance on the surface of neuronal cells define the tropism of distinct pathogenic alpha-synuclein assemblies toward defined cell populations within the CNS or to defined membranous structures (e.g. lipid rafts). The tropism of structurally distinct preformed fibrillar polymorphs for different neuronal cells is illustrated by the observation made in vivo that different a-synuclein strains target preferentially neurons or oligodendrocytes triggering Lewy body and neurite formation in neurons and/or yielding inclusions characteristic of multiple system atrophy in oligodendrocytes [55]. A time-dependent clustering of alpha-synuclein assemblies was reported after their diffusion within the cell membrane and interaction with their partners at the plasma membrane. The preferential clustering of alpha-synuclein assemblies around curved membranous structures such as synapses could be either due to their higher affinity for defined membrane geometry [8] or to partner molecules enriched within these structures. This affects the dynamic properties of partner molecules and membrane geometry which in turn favors both the redistribution of these partners and that of
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associated proteins, leading through a snowball effect to aberrant, non-physiological distribution and, eventually, pathological gain or loss of signaling functions [72]. After binding, structurally distinct alpha-synuclein assemblies are taken up mostly through endocytosis [73]. They are directed towards the lysosomal compartment. A fraction appears to escape during membrane fusion events and/or lysosomal membrane disruption [74,75]. This fraction highly depends on distinct alpha-synuclein assemblies exposing different polypeptide chains at their surfaces for their ability to resist the clearance machinery within the lysosomes. Within the cytosol, distinct alpha-synuclein assembly polymorphs interact with diverse protein partners in a manner dependent on their surfaces. Such interactions are expected to imbalance proteostasis to different extents following the titration of cytosolic molecular chaperones and/or saturation of the cell’s clearance machinery [76,77]. Other partner proteins may also get trapped in non-functional states. Furthermore, distinct alpha-synuclein polymorphs grow and amplify till exhaustion of their functional cytosolic form in a manner dependent on the extent to which the specific alpha-synuclein conformers they recruit are populated and on their recruitment efficiency [48,50]. Finally, within the cytosol, exogenous or amplified alphasynuclein polymorphs certainly interact with the mitochondrial, Golgi and endoplasmic reticulum membranes to different degrees, leading to organelle dysfunctions [78–83]. An additional factor that defines the type of synucleinopathy may be the degree of co-existence of alpha-synuclein and other pathogenic protein inclusions, in particular tau inclusions. Indeed, a wide range of synucleinopathies such as PD
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with dementia (PDD), DLB, Lewy body variant of Alzheimer’s disease (LBVAD), Guam-Parkinson-ALS dementia complex or Down’s syndrome and more than 50% of Alzheimer disease cases are characterized by the co-occurrence of alphasynuclein and tau inclusions, suggesting that there is a considerable crosstalk between these diseases [84,85]. This suggests that the co-existence of alpha-synuclein and tau inclusions as ‘‘teammates in neurodegeneration’’ [76] is the rule and not the exception and underlines the impact of proteostasis imbalance in distinct synucleinopathies. The amino acid stretches exposed at distinct alphasynuclein assembly extremities dictate their ability to grow and their interactomes, respectively. The ends of alphasynuclein high-molecular-weight polymorphs define the rate at which they elongate by recruitment of alpha-synuclein molecules in conformations that can establish highly complementary interactions. The rate at which functional alphasynuclein is exhausted in cells after aggregation contributes to disease phenotype. Thus, by recruiting their soluble alphasynuclein and depleting the cells from the functional form of the protein with different efficiencies, pathogenic alphasynuclein seeds define the speed at which synucleinopathies evolve as a function of time/age. The sides of pathogenic alpha-synuclein assemblies play a central role in disease [86] as they modulate:
their capacity to interact laterally to form bundles through hydrophobic or electrostatic interactions or via interaction with bridging cellular proteins;
Fig. 3 – The different fibrillar polymorphs alpha-synuclein conformations dictate. Natively unfolded alpha-synuclein (A), adopts a beta-strand-rich conformation (B), that can fold in space into different theoretical tertiary structures (C). One such conformation derived from solid-state NMR measurements is shown (D). Te molecules establish inter-molecular hydrogen bonds allowing them to pile up to constitute the fibrillar core (E, top and side views). One such fibrillar scaffold derived from solid-state NMR measurements [67] is shown (F). Dynamic N- and C-terminal amino acid stretches may project from the amyloid fibrillar core (F). A recent fibrillar structure, obtained by cryo-electron microscopy [68] reveals not only that the fibrillar core is constituted by two back-to back protofilaments (G) as opposed to one (F) but also an alpha-synuclein fold different from that derived from solid-state NMR measurements [67].
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their ability to form macromolecular structures within neuronal cells; their resistance to degradation and the cellular clearance machinery; their ability to be post-translationally modified or not; their interaction with partner proteins within the membrane and the cytosol and the redistribution of the latter; the rate at which they escape from the endo-lysosomal compartment after their uptake from the extracellular milieu; their capacity to interact with different cargos and molecular motors and to be transported anterogradely and retrogradely within neurons and; their ability to traffic/propagate from cell to cell through tunneling nanotubes [87–89], through synapses [53] or upon active export and import (exo- and endocytosis) [90,91] (Fig. 3). Besides determining the ability of pathologic protein assemblies to associate laterally and clearance propensity, depending on whether they expose proteolytic cleavage sites or not, the amino acid stretches exposed on the sides of pathologic protein assemblies define their interactomes. The full interactomes of pathogenic protein aggregates whether in the cytoplasm or at the plasma membrane is far from being fully identified. Nonetheless, it is reasonable to consider that different polymorphs are capable of interacting with overlapping but distinct partner protein ensembles and that the interactions lead to a redistribution of these partners, their possible loss of function upon the formation of different alpha-synuclein polymorph-partner protein complexes, and subsequent pathologies. The consequence of differential growth rates, bundling and resistance to degradation of exogenous alpha-synuclein strains has been assessed in vitro and in vivo. Different fulllength alpha-synuclein strains, seeded reporter alpha-synuclein aggregation in cultured cells, and aggregate persistence over generations after single exposure to the strains vary to very different extents [48]. Distinct strains were found to trigger aggregation of endogenous alpha-synuclein within rodents to different extents and imprinted their intrinsic structural characteristics [55]. Altogether these observations suggest that different strains exhibit different tropisms to cell populations within the CNS through the surfaces they expose and partners they interact with. This can lead to different distributions and phenotypes in distinct synucleinopathies.
Disclosure of interest The author declares that he has no competing interest.
Acknowledgements Research carried out in RM laboratory is sponsored by the Centre National de la Recherche Scientifique and grants from the Agence Nationale de la Recherche Scientifique, European
Commission Joint Programme on Neurodegenerative Diseases (JPND-Synaction JPND-TransPathND and JPND- PROTEST-70), Innovative Medicine Initiative 2 Joint grant agreement No 116060 (IMPRiND, www.imprind.org) supported by the European Union’s Horizon 2020 research and innovation program and EFPIA, the Institut de France-Fondation Simone et Cino Del Duca, the Fondation Bettencourt Schueller, the Fondation Pour La Recherche Me´dicale contract DEQ20160334896 and the Fondation de France.
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Please cite this article in press as: Melki R. Alpha-synuclein and the prion hypothesis in Parkinson’s disease. Revue neurologique (2018), https:// doi.org/10.1016/j.neurol.2018.08.002
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