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Amyloid fibrillar, but not soluble, histones induce intracellular αS aggregation upon internalization into recipient cells. H4/V1S-SV2(S)/LAMP1-eCFP/mCherry-Galectin-3 cells were treated with the same amount of soluble recombinant histone H1 and histone H1 amyloid fibrils, respectively. After 3 days of treatment, sibling cultures of each group were exposed to 1 mM LLME for 1–2 h. In parallel, a group of cells without histone, but with LLME treatment for the same time, were used as a control. (a) Cells in the individual groups were imaged under confocal microscope to detected intracellular αS inclusions. (b) Bar graph shows the comparison among different groups for the ratio of cells with inclusions to total cells. Error bars represent standard error of the mean (*p < 0.05, **p < 0.01, comparing subsets linked by line, n = 3). (c, d) For confirmation of histone H1 amyloid fibrils, samples were subjected to negative staining to demonstrate amyloid filaments with EM (c). Thioflavin T assay was also used to measure formation of beta-sheet structure (d). The same concentration of soluble histone H1 solution was used as a negative control. Scale bar in (c): 20 nm
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Cell-to-cell transfer of α-synuclein (αS) is increasingly thought to play an important role in propagation of αS pathology, but mechanisms responsible for formation of initial αS seeds and factors facilitating their propagation remain unclear. We previously demonstrated that αS aggregates are formed rapidly in apoptotic neurons and that interaction...
Citations
... value of the Mascot algorithm). Serum amyloid P-component, histone, and vitronectin, which have been reported as amyloid signature proteins in humans and some animal species 1,21,22,28 , were detected at low levels in some samples, proving the presence of amyloid fibrils in the microdissected samples. Keratin 5, previously reported as an amyloid precursor protein in dogs 4 , was detected in animals 4 and 5, but at much lower levels than ApoE. ...
Apolipoprotein E (ApoE) is involved in cholesterol transport among cells and also plays an important role in amyloid formation, co-depositing with amyloid fibrils in various types of amyloidosis. Although the in vivo amyloidogenicity of ApoE has not been previously demonstrated, this study provides evidence of ApoE amyloidogenicity in leopard geckos (Eublepharis macularius), belonging to the class Reptilia. Histologically, amyloid deposits were localized within cholesterol granulomas and exhibited positive Congo red staining, with yellow to green birefringence under polarized light. On mass spectrometry-based proteomic analysis, ApoE was detected as a dominant component of amyloid; of the full length of the 274 amino acid residues, peptides derived from Leu185-Arg230 were frequently detected with non-tryptic truncations. Immunohistochemistry with anti-leopard gecko ApoE antibody showed positive reactions of amyloid deposits. These results show that ApoE is an amyloid precursor protein within the cholesterol granulomas of leopard geckos. Although further investigations are needed, the C-terminal region of ApoE involved in amyloid formation is a lipid-binding region, and there should be a relationship between amyloidogenesis and the development of cholesterol granulomas in leopard geckos. This study provides novel insights into the pathogenesis of ApoE-related diseases.
... In the context of (pathological) protein aggregate formation, it should be noted that alpha-synuclein may form complexes with histones, protein components of chromatin, which play a key role in many cellular events [51]. Jiang et al. demonstrated the formation of such complexes and identified histones as proaggregant agents for alpha-synuclein aggregation in postmortem brains with Lewy body pathology [52,53]. Jos et al. reported that PD-specific alpha-synuclein bound histones H2A, H2B, H3, and H4 with higher affinity than wild-type alpha-synuclein [54]. ...
Ubiquitination (the covalent attachment of ubiquitin molecules to target proteins) is one of the main post-translational modifications of proteins. Historically, the type of polyubiquitination, which involves K48 lysine residues of the monomeric ubiquitin, was the first studied type of ubiquitination. It usually targets proteins for their subsequent proteasomal degradation. All the other types of ubiquitination, including monoubiquitination; multi-monoubiquitination; and polyubiquitination involving lysine residues K6, K11, K27, K29, K33, and K63 and N-terminal methionine, were defined as atypical ubiquitination (AU). Good evidence now exists that AUs, participating in the regulation of various cellular processes, are crucial for the development of Parkinson’s disease (PD). These AUs target various proteins involved in PD pathogenesis. The K6-, K27-, K29-, and K33-linked polyubiquitination of alpha-synuclein, the main component of Lewy bodies, and DJ-1 (another PD-associated protein) is involved in the formation of insoluble aggregates. Multifunctional protein kinase LRRK2 essential for PD is subjected to K63- and K27-linked ubiquitination. Mitophagy mediated by the ubiquitin ligase parkin is accompanied by K63-linked autoubiquitination of parkin itself and monoubiquitination and polyubiquitination of mitochondrial proteins with the formation of both classical K48-linked ubiquitin chains and atypical K6-, K11-, K27-, and K63-linked polyubiquitin chains. The ubiquitin-specific proteases USP30, USP33, USP8, and USP15, removing predominantly K6-, K11-, and K63-linked ubiquitin conjugates, antagonize parkin-mediated mitophagy.
