Spreading of α-Synuclein and Tau: A Systematic Comparison of the Mechanisms Involved

Vasili, Eftychia; Dominguez-Meijide, Antonio; Outeiro, Tiago F.

doi:10.3389/fnmol.2019.00107

Cited by 87 publications

(82 citation statements)

References 296 publications

(309 reference statements)

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“…Microvesicles or ectosomes might be also involved in tau spreading [199]. The mechanisms of the propagation of tau in cellular and animal models of diseases have been recently reviewed [200]. No possible receptors have been found that facilitate tau internalization, rather it occurs via macropinocytosis.…”

Section: Pathophysiological Effects Of Tau Assembliesmentioning

confidence: 99%

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

2020

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The structural polymorphism and the physiological and pathophysiological roles of two important proteins, β-amyloid (Aβ) and tau, that play a key role in Alzheimer’s disease (AD) are reviewed. Recent results demonstrate that monomeric Aβ has important physiological functions. Toxic oligomeric Aβ assemblies (AβOs) may play a decisive role in AD pathogenesis. The polymorph fibrillar Aβ (fAβ) form has a very ordered cross-β structure and is assumed to be non-toxic. Tau monomers also have several important physiological actions; however, their oligomerization leads to toxic oligomers (TauOs). Further polymerization results in probably non-toxic fibrillar structures, among others neurofibrillary tangles (NFTs). Their structure was determined by cryo-electron microscopy at atomic level. Both AβOs and TauOs may initiate neurodegenerative processes, and their interactions and crosstalk determine the pathophysiological changes in AD. TauOs (perhaps also AβO) have prionoid character, and they may be responsible for cell-to-cell spreading of the disease. Both extra- and intracellular AβOs and TauOs (and not the previously hypothesized amyloid plaques and NFTs) may represent the novel targets of AD drug research.

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Section: Pathophysiological Effects Of Tau Assembliesmentioning

confidence: 99%

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

2020

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“…When examined several years later, these patients showed signs of disease development in the grafted tissue, indicating that pathological α-syn had spread from diseased to healthy tissue (Kordower et al, 2008 ; Li et al, 2008 ). Various animal and cell culture models have confirmed the existence of such intercellular dissemination of α-syn (Jucker and Walker, 2013 ; Vasili et al, 2019 ).…”

Section: The Role Of Chaperones In Prion-like Propagationmentioning

confidence: 94%

Molecular Chaperones: A Double-Edged Sword in Neurodegenerative Diseases

Tittelmeier

Nachman

Nussbaum-Krammer

2020

Front. Aging Neurosci.

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Aberrant accumulation of misfolded proteins into amyloid deposits is a hallmark in many age-related neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). Pathological inclusions and the associated toxicity appear to spread through the nervous system in a characteristic pattern during the disease. This has been attributed to a prion-like behavior of amyloid-type aggregates, which involves self-replication of the pathological conformation, intercellular transfer, and the subsequent seeding of native forms of the same protein in the neighboring cell. Molecular chaperones play a major role in maintaining cellular proteostasis by assisting the (re)-folding of cellular proteins to ensure their function or by promoting the degradation of terminally misfolded proteins to prevent damage. With increasing age, however, the capacity of this proteostasis network tends to decrease, which enables the manifestation of neurodegenerative diseases. Recently, there has been a plethora of studies investigating how and when chaperones interact with disease-related proteins, which have advanced our understanding of the role of chaperones in protein misfolding diseases. This review article focuses on the steps of prion-like propagation from initial misfolding and self-templated replication to intercellular spreading and discusses the influence that chaperones have on these various steps, highlighting both the positive and adverse consequences chaperone action can have. Understanding how chaperones alleviate and aggravate disease progression is vital for the development of therapeutic strategies to combat these debilitating diseases.

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“…The available cellular models range from powerful yeast cells, to neuronal and non‐neuronal mammalian cell lines (human and non‐human), primary neuronal cultures and, more recently, patient‐derived iPS cells, to name just a few (Delenclos et al, ; Marvian, Koss, Aliakbari, Morshedi, & Outeiro, ). Different aSyn expression systems have also been employed, enabling transient or stable expression of either wild‐type or PD‐associated mutant forms of aSyn (Delenclos et al, ; Lazaro, Pavlou, & Outeiro, ; Vasili, Dominguez‐Meijide, & Outeiro, ). The use of cellular models affords numerous advantages, such as the ease of use and manipulation, both genetically and pharmacologically, the low maintenance costs, and the reduced ethical constraints.…”

Section: Cell Models Of Asyn Toxicity and Aggregationmentioning

confidence: 99%

Synucleinopathies: Where we are and where we need to go

Brás

Dominguez-Meijide

Gerhardt

et al. 2020

Journal of Neurochemistry

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All authors contributed equally to this manuscript. This artic le is relat ed to the Speci al Issue "Synuc lein" Abbreviations: A30P, aSyn substitution of an alanine for a proline at position 30; A53E, aSyn substitution of an alanine for a glutamic acid at position 53; A53T, aSyn substitution of an alanine for a tyrosine at position 53; ALP, autophagy-lysosomal pathway; APLP1, Aβ precursor-like protein 1; aSyn, alpha-synuclein; BiFC, bimolecular fluorescence complementation; CMA, Chaperone-mediated autophagy; CNS, central nervous system; co-IP, co-immunoprecipitation; Cryo-EM, cryo-electron microscopy; CSF, cerebrospinal fluid; Cu, copper; DLB, dementia with Lewy bodies; E46K, aSyn substitution of a glutamic acid for a lysine at position 46; ENS, enteric nervous system; ER, endoplasmic reticulum; Fe, iron; FRET, fluorescence resonance energy transfer; G51D, aSyn substitution of a glycine for a aspartic acid at position 51Abstract Synucleinopathies are a group of disorders characterized by the accumulation of inclusions rich in the a-synuclein (aSyn) protein. This group of disorders includes Parkinson's disease, dementia with Lewy bodies (DLB), multiple systems atrophy, and pure autonomic failure (PAF). In addition, genetic alterations (point mutations and multiplications) in the gene encoding for aSyn (SNCA) are associated with familial forms of Parkinson's disease, the most common synucleinopathy. The Synuclein Meetings are a series that has been taking place every 2 years for about 12 years. The Synuclein Meetings bring together leading experts in the field of Synuclein and related human conditions with the goal of discussing and advancing the research. In 2019, the Synuclein meeting took place in Ofir, a city in the outskirts of Porto, Portugal. The meeting, entitled "Synuclein Meeting 2019:Where we are and where we need to go", brought together >300 scientists studying both clinical and molecular aspects of synucleinopathies. The meeting covered a many of the open questions in the field, in a format that prompted open discussions between the participants, and underscored the need for additional research that, hopefully, will lead to future therapies for a group of as of yet incurable disorders. Here, we provide a summary of the topics discussed in each session and highlight what we know, what we do not know, and what progress needs to be made in order to enable the field to continue to advance. We are confident this systematic assessment of where we stand will be useful to steer the field and contribute to filling knowledge gaps that may form the foundations for future therapeutic strategies, which is where we need to go.

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Spreading of α-Synuclein and Tau: A Systematic Comparison of the Mechanisms Involved

Cited by 87 publications

References 296 publications

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

Molecular Chaperones: A Double-Edged Sword in Neurodegenerative Diseases

Synucleinopathies: Where we are and where we need to go

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