Structure, function and toxicity of alpha‐synuclein: the Bermuda triangle in synucleinopathies

Villar‐Piqué, Anna; Fonseca, Tomás Lopes da; Outeiro, Tiago F.

doi:10.1111/jnc.13249

Cited by 184 publications

(168 citation statements)

References 215 publications

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“…246 High resolution ion-mobility mass spectroscopy has revealed that HPLC-purified αS is autoproteolytic, giving rise to a number of small molecular weight fragments upon incubation. In particular, the fragment of residues 72–140 contains majority of the NAC region and aggregates faster than full-length αS.…”

Section: Alpha-synuclein and Parkinson’s Diseasementioning

confidence: 99%

Implications of peptide assemblies in amyloid diseases

et al. 2017

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Neurodegenerative disorders and type 2 diabetes are global epidemics compromising the quality of life of millions worldwide, with profound social and economic implications. Despite the significant differences in pathology – much of which are poorly understood – these diseases are commonly characterized by the presence of cross-β amyloid fibrils as well as the loss of neuronal or pancreatic β-cells. In this review, we document research progress on the molecular and mesoscopic self-assembly of amyloid-beta, alpha synuclein, human islet amyloid polypeptide and prions, the peptides and proteins associated with Alzheimer’s, Parkinson’s, type 2 diabetes and prions diseases. In addition, we discuss the toxicities of these amyloid proteins based on their self-assembly as well as their interactions with membranes, metal ions, small molecules and engineered nanoparticles. Through this presentation we show the remarkable similarities and differences in the structural transitions of the amyloid proteins through primary and secondary nucleation, the common evolution from disordered monomers to alpha-helices and then to β-sheets when the proteins encounter the cell membrane, and, the consensus (with a few exceptions) that off-pathway oligomers, rather than amyloid fibrils, are the toxic species regardless of the pathogenic protein sequence or physicochemical properties. In addition, we highlight the crucial role of molecular self-assembly in eliciting the biological and pathological consequences of the amyloid proteins within the context of their cellular environments and their spreading between cells and organs. Exploiting such structure-function-toxicity relationship may prove pivotal for the detection and mitigation of amyloid diseases.

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Section: Alpha-synuclein and Parkinson’s Diseasementioning

confidence: 99%

Implications of peptide assemblies in amyloid diseases

et al. 2017

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“…LNs are abnormal neuronal processes (axons or dendrites) that contain α-syn aggregates with a more diffuse α-syn morphology than LBs. LBs and LNs are the primary pathological features of the Lewy body diseases (LBD) (229, 230). In addition, aggregated α-syn is also a major constituent of oligodendrocyte glial cytoplasmic inclusions (GCIs) found in MSA (231).…”

Section: α-Synucleinopathiesmentioning

confidence: 99%

Small-molecule PET Tracers for Imaging Proteinopathies

Mathis

Lopresti

Ikonomović

et al. 2017

Seminars in Nuclear Medicine

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In this chapter, we provide a review of the challenges and advances in developing successful positron emission tomography (PET) imaging agents for three major types of aggregated amyloid proteins – amyloid-beta (Aβ), tau, and alpha-synuclein (α-syn). These three amyloids are involved in the pathogenesis of a variety of neurodegenerative diseases, referred to as proteinopathies or proteopathies, that include Alzheimer’s disease, Lewy body dementias, multiple system atrophy, and frontal temporal dementias among others. In the Introduction, we briefly discuss the history of amyloid in neurodegenerative diseases and describe why progress in developing effective imaging agents has been hampered by the failure of crystallography to provide definitive ligand-protein interactions for rational radioligand design efforts. Instead, the field has relied on largely serendipitous, trial and error methods to achieve useful and specific PET amyloid imaging tracers for Aβ, tau, and α-syn deposits. Because many of the proteopathies involve more than one amyloid protein, it is important to develop selective PET tracers for the different amyloids to help assess the relative contribution of each to total amyloid burden. We utilize Pittsburgh Compound B (PiB) to illustrate some of the critical steps in developing a potent and selective Aβ PET imaging agent. Other selective Aβ and tau PET imaging compounds have followed similar pathways in their developmental processes. Success for selective α-syn PET imaging agents has not been realized yet, but work is ongoing in multiple laboratories throughout the world. In the tau sections, we provide background regarding 3-repeat (3R) and 4-repeat (4R) tau proteins and how they can affect the binding of tau radioligands in different tauopathies. We review the ongoing efforts to assess the properties of tau ligands, which are useful in 3R, 4R or combined 3R/4R tauopathies. Finally, we describe in the α-syn sections recent attempts to develop selective tracers to image α-synucleinopathies.

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“…Aggregation of α -synuclein is a critical step in the etiology of PD, with prefibrillar oligomers of the protein that might constitute the direct precursors of fibrils being involved in neurodegenerative process [87, 88]. Even if the injection of fibrils into the rat brain is found to be more toxic than that of oligomers and ribbons, as it induces neurodegeneration and motor impairment, all these species can self-amplify in vivo and lead to PD/multiple system atrophy-like alterations in the injected animals [89].…”

Section: Toxicity Of α-Synuclein Oligomers and Fibrils: A Still Unmentioning

confidence: 99%

The Contribution ofα-Synuclein Spreading to Parkinson’s Disease Synaptopathy

et al. 2017

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Synaptopathies are diseases with synapse defects as shared pathogenic features, encompassing neurodegenerative disorders such as Parkinson's disease (PD). In sporadic PD, the most common age-related neurodegenerative movement disorder, nigrostriatal dopaminergic deficits are responsible for the onset of motor symptoms that have been related to α-synuclein deposition at synaptic sites. Indeed, α-synuclein accumulation can impair synaptic dopamine release and induces the death of nigrostriatal neurons. While in physiological conditions the protein can interact with and modulate synaptic vesicle proteins and membranes, numerous experimental evidences have confirmed that its pathological aggregation can compromise correct neuronal functioning. In addition, recent findings indicate that α-synuclein pathology spreads into the brain and can affect the peripheral autonomic and somatic nervous system. Indeed, monomeric, oligomeric, and fibrillary α-synuclein can move from cell to cell and can trigger the aggregation of the endogenous protein in recipient neurons. This novel “prion-like” behavior could further contribute to synaptic failure in PD and other synucleinopathies. This review describes the major findings supporting the occurrence of α-synuclein pathology propagation in PD and discusses how this phenomenon could induce or contribute to synaptic injury and degeneration.

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Structure, function and toxicity of alpha‐synuclein: the Bermuda triangle in synucleinopathies

Cited by 184 publications

References 215 publications

Implications of peptide assemblies in amyloid diseases

Implications of peptide assemblies in amyloid diseases

Small-molecule PET Tracers for Imaging Proteinopathies

The Contribution ofα-Synuclein Spreading to Parkinson’s Disease Synaptopathy

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