The many faces of α-synuclein: from structure and toxicity to therapeutic target

Lashuel, Hilal A.; Overk, Cassia R.; Oueslati, Abid; Masliah, Eliezer

doi:10.1038/nrn3406

Cited by 1,424 publications

(1,480 citation statements)

References 129 publications

(176 reference statements)

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“…Most recent evidence suggests that oligomers and probably also protofibrils are toxic to neurons by disrupting synaptic function, membrane permeability, calcium homeostasis, gene transcription, mitochondrial activity, autophagy, and/or endosomal transport [18][19][20][21]. Moreover, recent studies have shown that propagation and seeding of Aβ, tau, and α-syn in a prion-like manner might also contribute to neurodegeneration [22][23][24][25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

2016

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Disease-modifying alternatives are sorely needed for the treatment of neurodegenerative disorders, a group of diseases that afflict approximately 50 million Americans annually. Immunotherapy is one of the most developed approaches in this direction. Vaccination against amyloid-β, α-synuclein, or tau has been extensively explored, specially as the discovery that these proteins may propagate cell-to-cell and be accessible to antibodies when embedded into the plasma membrane or in the extracellular space. Likewise, the use of passive immunization approaches with specific antibodies against abnormal conformations of these proteins has also yielded promising results. The clinical development of immunotherapies for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, and other neurodegenerative disorders is a field in constant evolution. Results to date suggest that immunotherapy is a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and prion-like propagation of toxic protein aggregates. Here we provide an overview of the most novel and relevant immunotherapeutic advances targeting amyloid-β in Alzheimer's disease, α-synuclein in Alzheimer's disease and Parkinson's disease, and tau in Alzheimer's disease and frontotemporal dementia.

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Section: Introductionmentioning

confidence: 99%

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

2016

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“…α-Synuclein (α-syn) instigates both sporadic and idiopathic Parkinson's disease (PD) by various modes of action [1] and is the major component of intracellular Lewy bodies and Lewy neurites in the brain [2]. The three rare missense mutations of α-syn (A30P, A53T and E46K), copy number variants and two probable substitutions (H50Q and G51D) are associated with familial PD, indicating a central role for this protein [3].…”

Section: Introductionmentioning

confidence: 99%

“…The morphology and associated mode of toxicity displayed by alternative types of α-syn oligomers are largely dependent on the environmental conditions under which they have been prepared [6][7][8][9][10][11]. Numerous in vitro and in vivo studies on α-syn oligomers have demonstrated that a toxic gain-offunction occurs in the disease state via two main mechanisms: (i) Ca 2 + imbalances caused by the formation of pore-like complexes within lipid membranes, and (ii) transmembrane seeding that then results in intracellular aggregation [1]. α-Syn is expressed as an intracellular protein but has been shown to be directly secreted or released as a result of neuronal death or stress conditions into the extracellular space [12].…”

Section: Introductionmentioning

confidence: 99%

Distinct higher-order α-synuclein oligomers induce intracellular aggregation

Illes‐Toth

Ramos

Cappai

et al. 2015

Biochemical Journal

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Misfolding and aggregation of α-synuclein (α-syn) into Lewy bodies is associated with a range of neurological disorders, including Parkinson's disease (PD). The cell-to-cell transmission of α-syn pathology has been linked to soluble amyloid oligomer populations that precede Lewy body formation. Oligomers produced in vitro under certain conditions have been demonstrated to induce intracellular aggregation in cell culture models. In the present study, we characterize, by ESI-ion mobility spectrometry (IMS)-MS, a specific population of α-syn oligomers. These MS-compatible oligomers were compared with oligomers with known seeding and pore-forming capabilities and were shown to have the ability to induce intracellular aggregation. Each oligomer type was shown to have distinct epitope profiles that correlated with their toxic gain-of-function. Structurally, the MS compatible oligomers populated a range of species from dimers through to hexamers. Lower-order oligomers were structurally diverse and consistent with unstructured assemblies. Higher-order oligomers were shown to be compact with ring-like structures. The observation of this compact state may explain how this natively disordered protein is able to transfer pathology from cell to cell and avoid degradation by cellular proteases.

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“…The processes of α‐synuclein oligomerization and fibril growth play central roles in the pathogenesis of Parkinson's disease (Lashuel et al . 2013) and are influenced by monoubiquitylation. Monoubiquitylation by the E3 ligase SIAH (at K10, K12, K21, K23, K34, K43 or K96) promotes α‐synuclein aggregation (Rott et al .…”

Section: Regulation Of Neuronal Proteins By Monoubiquitylationmentioning

confidence: 99%

Protein monoubiquitylation: targets and diverse functions

Nakagawa

Nakayama

2015

Genes to Cells

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Ubiquitin is a 76‐amino acid protein whose conjugation to protein targets is a form of post‐translational modification. Protein ubiquitylation is characterized by the covalent attachment of the COOH‐terminal carboxyl group of ubiquitin to an amino group of the substrate protein. Given that the NH2‐terminal amino group is usually masked, internal lysine residues are most often targeted for ubiquitylation. Polyubiquitylation refers to the formation of a polyubiquitin chain on the substrate as a result of the ubiquitylation of conjugated ubiquitin. The structures of such polyubiquitin chains depend on the specific lysine residues of ubiquitin targeted for ubiquitylation. Most of the polyubiquitin chains other than those linked via lysine‐63 and methionine‐1 of ubiquitin are recognized by the proteasome and serve as a trigger for substrate degradation. In contrast, polyubiquitin chains linked via lysine‐63 and methionine‐1 serve as a binding platform for proteins that function in immune signal transduction or DNA repair. With the exception of a few targets such as histones, the functions of protein monoubiquitylation have remained less clear. However, recent proteomics analysis has shown that monoubiquitylation occurs more frequently than polyubiquitylation, and studies are beginning to provide insight into its biologically important functions. Here, we summarize recent findings on protein monoubiquitylation to provide an overview of the targets and molecular functions of this modification.

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The many faces of α-synuclein: from structure and toxicity to therapeutic target

Cited by 1,424 publications

References 129 publications

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

Distinct higher-order α-synuclein oligomers induce intracellular aggregation

Protein monoubiquitylation: targets and diverse functions

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