Dynamic behaviors of α-synuclein and tau in the cellular context: New mechanistic insights and therapeutic opportunities in neurodegeneration

Yeboah, Fred; Kim, Tae‐Eun; Bill, Anke; Dettmer, Ulf

doi:10.1016/j.nbd.2019.104543

Cited by 18 publications

(18 citation statements)

References 213 publications

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“…In addition, positivelycharged lysine residues (K) in the KTKEGV motifs interact with negatively-charged membrane lipid head groups [56]. Yet, the helix formation is imperfect and only transient because, e.g., polar threonine (T) residues are located in the hydrophobic half of the helix [57][58][59]. A recent in vitro study suggests that ␣Syn coming off the membrane may retain its fold and assemble into helical multimers [60] (see next chapter).…”

Section: Lipid Bindingmentioning

confidence: 99%

Soluble endogenous oligomeric α-synuclein species in neurodegenerative diseases: Expression, spreading, and cross-talk

Kayed

Dettmer

Lesné

2020

JPD

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There is growing recognition in the field of neurodegenerative diseases that mixed proteinopathies are occurring at greater frequency than originally thought. This is particularly true for three amyloid proteins defining most of these neurological disorders, amyloid-beta (A␤), tau, and alpha-synuclein (␣Syn). The coexistence and often co-localization of aggregated forms of these proteins has led to the emergence of concepts positing molecular interactions and cross-seeding between A␤, tau, and ␣Syn aggregates. Amongst this trio, ␣Syn has received particular attention in this context during recent years due to its ability to modulate A␤ and tau aggregation in vivo, to interact at a molecular level with A␤ and tau in vivo and to cross-seed tau in mice. Here we provide a comprehensive, critical, and accessible review about the expression, role and nature of endogenous soluble ␣Syn oligomers because of recent developments in the understanding of ␣Syn multimerization, misfolding, aggregation, cross-talk, spreading and cross-seeding in neurodegenerative disorders, including Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Alzheimer's disease, and Huntington's disease. We will also discuss our current understanding about the relative toxicity of endogenous ␣Syn oligomers in vivo and in vitro, and introduce potential opportunities to counter their deleterious effects.

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Section: Lipid Bindingmentioning

confidence: 99%

Soluble endogenous oligomeric α-synuclein species in neurodegenerative diseases: Expression, spreading, and cross-talk

Kayed

Dettmer

Lesné

2020

JPD

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“…The role of tau in MT stabilization and spatial organization has been thoroughly studied [158][159][160]. Tau plays a pivotal role in MT stabilization: it binds transiently to the C-terminal end of tubulin and drives polymerization of the protein to MTs [140,161,162]. Tau phosphorylation regulates tubulin binding to MTs [163,164].…”

Section: Physiological Actions Of Taumentioning

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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“…α-Synuclein (a product of the SNCA gene) is found mainly at presynaptic terminals of neurons. Studies indicate that α-synuclein plays a key role in restricting the mobility of synaptic vesicles, lessening neurotransmitter release and synaptic vesicle recycling [ 11 ]. Abnormal aggregates (inclusions and aggresomes) of wild-type or mutated α-synuclein may block the cellular functions associated with the degradation system, mitochondria, and chaperone proteins, resulting in a rapid loss of whole-cell homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Maackiain Ameliorates 6-Hydroxydopamine and SNCA Pathologies by Modulating the PINK1/Parkin Pathway in Models of Parkinson’s Disease in Caenorhabditis elegans and the SH-SY5Y Cell Line

Tsai

Liu

et al. 2020

IJMS

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The movement disorder Parkinson’s disease (PD) is the second most frequently diagnosed neurodegenerative disease, and is associated with aging, the environment, and genetic factors. The intracellular aggregation of α-synuclein and the loss of dopaminergic neurons in the substantia nigra pars compacta are the pathological hallmark of PD. At present, there is no successful treatment for PD. Maackiain (MK) is a flavonoid extracted from dried roots of Sophora flavescens Aiton. MK has emerged as a novel agent for PD treatment that acts by inhibiting monoamine oxidase B. In this study, we assessed the neuroprotective potential of MK in Caenorhabditis elegans and investigated possible mechanism of this neuroprotection in the human SH-SY5Y cell line. We found that MK significantly reduced dopaminergic neuron damage in 6-hydroxydopamine (6-OHDA)-exposed worms of the BZ555 strain, with corresponding improvements in food-sensing behavior and life-span. In transgenic worms of strain NL5901 treated with 0.25 mM MK, the accumulation of α-synuclein was diminished by 27% (p < 0.01) compared with that in untreated worms. Moreover, in worms and the SH-SY5Y cell line, we confirmed that the mechanism of MK-mediated protection against PD pathology may include blocking apoptosis, enhancing the ubiquitin-proteasome system, and augmenting autophagy by increasing PINK1/parkin expression. The use of small interfering RNA to downregulate parkin expression in vivo and in vitro could reverse the benefits of MK in PD models. MK may have considerable therapeutic applications in PD.

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Dynamic behaviors of α-synuclein and tau in the cellular context: New mechanistic insights and therapeutic opportunities in neurodegeneration

Cited by 18 publications

References 213 publications

Soluble endogenous oligomeric α-synuclein species in neurodegenerative diseases: Expression, spreading, and cross-talk

Soluble endogenous oligomeric α-synuclein species in neurodegenerative diseases: Expression, spreading, and cross-talk

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

Maackiain Ameliorates 6-Hydroxydopamine and SNCA Pathologies by Modulating the PINK1/Parkin Pathway in Models of Parkinson’s Disease in Caenorhabditis elegans and the SH-SY5Y Cell Line

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