Dataset Information

Increased Dynamics of ?-Synuclein Fibrils by ?-Synuclein Leads to Reduced Seeding and Cytotoxicity.

ABSTRACT: Alpha-synuclein (?S) fibrils are toxic to cells and contribute to the pathogenesis and progression of Parkinson's disease and other synucleinopathies. ?-Synuclein (?S), which co-localizes with ?S, has been shown to provide a neuroprotective effect, but the molecular mechanism by which this occurs remains elusive. Here we show that ?S fibrils formed in the presence of ?S are less cytotoxic, exhibit reduced cell seeding capacity and are more resistant to fibril shedding compared to ?S fibrils alone. Using solid-state NMR, we found that the overall structure of the core of ?S fibrils when co-incubated with ?S is minimally perturbed, however, the dynamics of Lys and Thr residues, located primarily in the imperfect KTKEGV repeats of the ?S N-terminus, are increased. Our results suggest that amyloid fibril dynamics may play a key role in modulating toxicity and seeding. Thus, enhancing the dynamics of amyloid fibrils may be a strategy for future therapeutic targeting of neurodegenerative diseases.

SUBMITTER: Yang X

PROVIDER: S-EPMC6879756 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Publications

Increased Dynamics of α-Synuclein Fibrils by β-Synuclein Leads to Reduced Seeding and Cytotoxicity.

Yang Xue X Williams Jonathan K JK Yan Run R Mouradian M Maral MM Baum Jean J

Scientific reports 20191126 1

Alpha-synuclein (αS) fibrils are toxic to cells and contribute to the pathogenesis and progression of Parkinson's disease and other synucleinopathies. β-Synuclein (βS), which co-localizes with αS, has been shown to provide a neuroprotective effect, but the molecular mechanism by which this occurs remains elusive. Here we show that αS fibrils formed in the presence of βS are less cytotoxic, exhibit reduced cell seeding capacity and are more resistant to fibril shedding compared to αS fibrils alon ...[more]

PMID: 31772376

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Project description:The distinct neuropathological features of the different α-Synucleinopathies, as well as the diversity of the α-Synuclein (α-Syn) intracellular inclusion bodies observed in post mortem brain sections, are thought to reflect the strain diversity characterizing invasive α-Syn amyloids. However, this "one strain, one disease" view is still hypothetical, and to date, a possible disease-specific contribution of non-amyloid factors has not been ruled out. In Multiple System Atrophy (MSA), the buildup of α-Syn inclusions in oligodendrocytes seems to result from the terminal storage of α-Syn amyloid aggregates first pre-assembled in neurons. This assembly occurs at the level of neuronal cytoplasmic inclusions, and even earlier, within neuronal intranuclear inclusions (NIIs). Intriguingly, α-Syn NIIs are never observed in α-Synucleinopathies other than MSA, suggesting that these inclusions originate (i) from the unique molecular properties of the α-Syn fibril strains encountered in this disease, or alternatively, (ii) from other factors specifically dysregulated in MSA and driving the intranuclear fibrillization of α-Syn. We report the isolation and structural characterization of a synthetic human α-Syn fibril strain uniquely capable of seeding α-Syn fibrillization inside the nuclear compartment. In primary mouse cortical neurons, this strain provokes the buildup of NIIs with a remarkable morphology reminiscent of cat's eye marbles (see video abstract). These α-Syn inclusions form giant patterns made of one, two, or three lentiform beams that span the whole intranuclear volume, pushing apart the chromatin. The input fibrils are no longer detectable inside the NIIs, where they become dominated by the aggregation of endogenous α-Syn. In addition to its phosphorylation at S129, α-Syn forming the NIIs acquires an epitope antibody reactivity profile that indicates its organization into fibrils, and is associated with the classical markers of α-Syn pathology p62 and ubiquitin. NIIs are also observed in vivo after intracerebral injection of the fibril strain in mice. Our data thus show that the ability to seed NIIs is a strain property that is integrally encoded in the fibril supramolecular architecture. Upstream alterations of cellular mechanisms are not required. In contrast to the lentiform TDP-43 NIIs, which are observed in certain frontotemporal dementias and which are conditional upon GRN or VCP mutations, our data support the hypothesis that the presence of α-Syn NIIs in MSA is instead purely amyloid-strain-dependent.

Dataset Information

Increased Dynamics of ?-Synuclein Fibrils by ?-Synuclein Leads to Reduced Seeding and Cytotoxicity.

Publications

Increased Dynamics of α-Synuclein Fibrils by β-Synuclein Leads to Reduced Seeding and Cytotoxicity.

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