Binding of α-synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes

Reyes, Juan F.; Sackmann, Christopher; Hoffmann, Alana; Svenningsson, Per; Winkler, Jürgen; Ingelsson, Martin; Hallbeck, Martin

doi:10.1007/s00401-019-02007-x

Cited by 52 publications

(50 citation statements)

References 77 publications

(120 reference statements)

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“…Recent studies have shown that cell-to-cell spreading of the pathogenic protein aggregates is necessary for propagation of the diseases [94,95]. Heparan sulfate proteoglycans (HSPGs), a family of proteins containing one or more sulfated glycosaminoglycan (GAG) heparan sulfate (HS) have been shown to play an important role in cellular uptake of the aggregated proteins, such as fibrils of amyloid-β [96] and tau [97].…”

Section: Discussionmentioning

confidence: 99%

Polymorphic α-Synuclein Strains Modified by Dopamine and Docosahexaenoic Acid Interact Differentially with Tau Protein

et al. 2020

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The pathological hallmark of synucleinopathies, including Parkinson's disease (PD), is the aggregation of α-synuclein (α-Syn) protein. Even so, tau protein pathology is abundantly found in these diseases. Both α-Syn and tau can exist as polymorphic aggregates, a phenomenon that has been widely studied, mostly in their fibrillar assemblies. We have previously discovered that in addition to α-Syn oligomers, oligomeric tau is also present in the brain tissues of patients with PD and dementia with Lewy bodies (DLB). However, the effect of interaction between polymorphic α-Syn oligomers and tau has not been scrupulously studied. Here, we have explored the structural and functional diversity of distinct α-Syn oligomers, prepared by modifying the protein with dopamine (DA) and docosahexaenoic acid (DHA). The two α-Syn oligomers differed in aggregate size, conformation, sensitivity to proteinase K digestion, tryptic digestion, and toxicity, suggesting them as distinct α-Syn oligomeric strains. We examined their internalization mechanisms in primary neurons and seeding propensity in inducing α-Syn aggregation. Using a combined approach of molecular and cellular techniques, we observed that the tau aggregates cross-seeded with the individual α-Syn oligomeric strains differed in their biochemical and biological properties, suggesting two distinct tau strains. The tau aggregate cross-seeded with the DA-modified α-Syn oligomeric strain possessed a potent intracellular tau seeding propensity. This study provides a comprehensive analysis of unique strain-specific interaction between oligomeric α-Syn and tau. Furthermore, this study allows us to speculate that distinct α-Syn-tau interactions inducing tau aggregation might be an underlying mechanism of neurodegeneration in PD.

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Section: Discussionmentioning

confidence: 99%

Polymorphic α-Synuclein Strains Modified by Dopamine and Docosahexaenoic Acid Interact Differentially with Tau Protein

et al. 2020

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“…To do this, we used well characterized iPSC-derived ltNES cells, which upon differentiation, are electrophysiologically mature and display mature neuronal markers [14][15][16][17][18][19][20][21] . Since Aβ oligomers are thought to be the most relevant aggregates in AD pathology, we challenged the differentiated neurons with 1 µM oAβ over 24 h to mimic the early phase of oAβ challenge, similar to previous studies 22,23,[26][27][28][29][30] . Previous studies have shown that concentrations of up to 3 µM oAβ 1-42 exist within neurons of the AD brain 31 , while the concentrations of oAβ used in this study may reflect those in the immediate vicinity of amyloid plaque cores, the so-called halo region 32,33 .…”

Section: Discussionmentioning

confidence: 99%

Oligomeric amyloid-β induces early and widespread changes to the proteome in human iPSC-derived neurons

Sackmann

Hallbeck

2020

Sci Rep

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Alzheimer's disease (AD) is the most common form of dementia globally and is characterized by aberrant accumulations of amyloid-beta (Aβ) and tau proteins. oligomeric forms of these proteins are believed to be most relevant to disease progression, with oligomeric amyloid-β (oAβ) particularly implicated in AD. oAβ pathology spreads among interconnected brain regions, but how oAβ induces pathology in these previously unaffected neurons requires further study. Here, we use well characterized ipSc-derived human neurons to study the early changes to the proteome and phosphoproteome after 24 h exposure to oAβ 1-42. Using nLC-MS/MS and label-free quantification, we identified several proteins that are differentially regulated in response to acute oAβ challenge. At this early timepoint, oAβ induced the decrease of TDP-43, heterogeneous nuclear ribonucleoproteins (hnRNPs), and coatomer complex I (COPI) proteins. Conversely, increases were observed in 20 S proteasome subunits and vesicle associated proteins VAMP1/2, as well as the differential phosphorylation of tau at serine 208. These changes show that there are widespread alterations to the neuronal proteome within 24 h of oAβ uptake, including proteins previously not shown to be related to neurodegeneration. this study provides new targets for the further study of early mediators of AD pathogenesis.Alzheimer's disease (AD) is the most prevalent form of dementia globally and is expected to grow substantially along with the aging global population. Much of the research in this field has focused on the pathological hallmarks of AD, amyloid-β (Aβ) and tau, but the way in which these mediators initiate neuronal pathogenesis at the molecular level requires further understanding. An important consideration in the study of AD is the different properties of Aβ assemblies: monomers, oligomers and fibrils. In particular, there is growing evidence to suggest that low molecular weight Aβ oligomers (oAβ) and protofibrils seed the aggregation of naïve Aβ, confer neurotoxicity, and also correlate to cognitive decline, as reviewed in 1-4 . Much of our current understanding of AD comes from the study of long-term exposure to Aβ in animal models, which has provided valuable insight into the effects of chronic exposure to Aβ, but often overlook the initial steps involved in pathogenesis. In order to further our understanding of the acute effects of exposure to oAβ, we challenged human iPSC-derived neurons with oAβ for 24 h and examined the changes to the proteome and phosphoproteome elicited by this acute oAβ treatment. In this way, we aim to elucidate some of the early effects elicited by oAβ upon neurons.During AD, widespread changes occur in the proteome, including the up-and downregulation of disease-related proteins as well as the post-translational modification (PTM) of proteins. PTMs such as phosphorylation greatly affect the function of proteins and are well known to be important for the pathogenesis of neurodegenerative disorders, where detection of phosphorylated proteins are us...

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“…In addition to neurons, microglia were also involved in the intercellular transmission of α-syn oligomers, by secreting oligomers through exosomes and inducing α-syn accumulation in neurons [ 76 ]. While the exact mechanism of α-syn oligomers intercellular transfer is unclear, the gap junction protein connexin-32 (Cx32) was proved to preferentially ingest α-syn oligomers in neurons and oligodendrocytes [ 77 ].…”

Section: Prion Principle Of α-Syn Oligomersmentioning

confidence: 99%

The Role of α-Synuclein Oligomers in Parkinson’s Disease

Xie

Liu

2020

IJMS

135

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α-synuclein (α-syn) is a protein associated with the pathogenesis of Parkinson’s disease (PD), the second most common neurodegeneration disease with no effective treatment. However, how α-syn drives the pathology of PD remains elusive. Recent studies suggest that α-syn oligomers are the primary cause of neurotoxicity and play a critical role in PD. In this review, we discuss the process of α-syn oligomers formation and the current understanding of the structures of oligomers. We also describe seed and propagation effects of oligomeric forms of α-syn. Then, we summarize the mechanism by which α-syn oligomers exert neurotoxicity and promote neurodegeneration, including mitochondrial dysfunction, endoplasmic reticulum stress, proteostasis dysregulation, synaptic impairment, cell apoptosis and neuroinflammation. Finally, we investigate treatment regimens targeting α-syn oligomers at present. Further research is needed to understand the structure and toxicity mechanism of different types of oligomers, so as to provide theoretical basis for the treatment of PD.

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Binding of α-synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes

Cited by 52 publications

References 77 publications

Polymorphic α-Synuclein Strains Modified by Dopamine and Docosahexaenoic Acid Interact Differentially with Tau Protein

Polymorphic α-Synuclein Strains Modified by Dopamine and Docosahexaenoic Acid Interact Differentially with Tau Protein

Oligomeric amyloid-β induces early and widespread changes to the proteome in human iPSC-derived neurons

The Role of α-Synuclein Oligomers in Parkinson’s Disease

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