Cryo-EM structure of amyloid fibril formed by α-synuclein hereditary A53E mutation reveals a distinct protofilament interface.

Synucleinopathies like Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple systems atrophy (MSA), have the same pathologic feature of misfolded α-synuclein protein (α-syn) accumulation in the brain. PD patients who carry α-syn hereditary mutations tend to have earlier onset and more severe clinical symptoms than sporadic PD patients. Therefore, revealing the effect of hereditary mutations to the α-syn fibril structure can help us understand these synucleinopathies' structural basis. Here, we present a 3.38 Å cryo-electron microscopy structure of α-synuclein fibrils containing the hereditary A53E mutation. The A53E fibril is symmetrically composed of two protofilaments, similar to other fibril structures of WT and mutant α-synuclein. The new structure is distinct from all other synuclein fibrils, not only at the interface between proto-filaments, but also between residues packed within the same proto-filament. A53E has the smallest interface with the least buried surface area among all α-syn fibrils, consisting of only two contacting residues. Within the same protofilament, A53E reveals distinct residue re-arrangement and structural variation at a cavity near its fibril core. Moreover, the A53E fibrils exhibit slower fibril formation and lower stability compared to WT and other mutants like A53T and H50Q, while also demonstrate strong cellular seeding in α-synuclein biosensor cells and primary neurons. In summary, our study aims to highlight structural differences - both within and between the protofilaments of A53E fibrils - and interpret fibril formation and cellular seeding of α-synuclein pathology in disease, which could further our understanding of the structure-activity relationship of α-synuclein mutants.

Post-translational modifications of soluble α-synuclein regulate the amplification of pathological α-synuclein.

Cell-to-cell transmission and subsequent amplification of pathological proteins promote neurodegenerative disease progression. Most research on this has focused on pathological protein seeds, but how their normal counterparts, which are converted to pathological forms during transmission, regulate transmission is less understood. Here we show in cultured cells that phosphorylation of soluble, nonpathological α-synuclein (α-Syn) at previously identified sites dramatically affects the amplification of pathological α-Syn, which underlies Parkinson's disease and other α-synucleinopathies, in a conformation- and phosphorylation site-specific manner. We performed LC-MS/MS analyses on soluble α-Syn purified from Parkinson's disease and other α-synucleinopathies, identifying many new α-Syn post-translational modifications (PTMs). In addition to phosphorylation, acetylation of soluble α-Syn also modified pathological α-Syn transmission in a site- and conformation-specific manner. Moreover, phosphorylation of soluble α-Syn could modulate the seeding properties of pathological α-Syn. Our study represents the first systematic analysis how of soluble α-Syn PTMs affect the spreading and amplification of pathological α-Syn, which may affect disease progression.

Association of serum HDL-cholesterol and apolipoprotein A1 levels with risk of severe SARS-CoV-2 infection.

Individuals with features of metabolic syndrome are particularly susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus associated with the severe respiratory disease, coronavirus disease 2019 (COVID-19). Despite considerable attention dedicated to COVID-19, the link between metabolic syndrome and SARS-CoV-2 infection remains unclear. Using data from the UK Biobank, we investigated the relationship between severity of COVID-19 and metabolic syndrome-related serum biomarkers measured prior to SARS-CoV-2 infection. Logistic regression analyses were used to test biomarker levels and biomarker-associated genetic variants with SARS-CoV-2-related outcomes. Among SARS-CoV-2-positive cases and negative controls, a 10 mg/dl increase in serum HDL-cholesterol or apolipoprotein A1 levels was associated with ∼10% reduced risk of SARS-CoV-2 infection, after adjustment for age, sex, obesity, hypertension, type 2 diabetes, and coronary artery disease. Evaluation of known genetic variants for HDL-cholesterol revealed that individuals homozygous for apolipoprotein E4 alleles had ∼2- to 3-fold higher risk of SARS-CoV-2 infection or mortality from COVID-19 compared with apolipoprotein E3 homozygotes, even after adjustment for HDL-cholesterol levels. However, cumulative effects of all evaluated HDL-cholesterol-raising alleles and Mendelian randomization analyses did not reveal association of genetically higher HDL-cholesterol levels with decreased risk of SARS-CoV-2 infection. These results implicate serum HDL-cholesterol and apolipoprotein A1 levels measured prior to SAR-CoV-2 exposure as clinical risk factors for severe COVID-19 infection but do not provide evidence that genetically elevated HDL-cholesterol levels are associated with SAR-CoV-2 infection.

Nunataks or massif de refuge? A phylogeographic study of Rhodiola crenulata (Crassulaceae) on the world's highest sky islands.

BACKGROUND: Quaternary climatic oscillations had tremendous effects on the current distribution of species. Here, we aim to elucidate the glacial history of Rhodiola crenulata, a perennial herb almost exclusively restricted to rock crevices on mountain peaks, and to test whether the nunatak or massif de refuge hypotheses could explain its distribution pattern. RESULTS: Six haplotypes and six ribotypes were detected in the cpDNA data set and the ITS data set, respectively. The divergence of R. crenulata and its closest relatives was dated have occurred ca. 0.65 Mya, during the Naynayxungla glaciation on the QTP. Mismatch distribution analysis suggested that the species experienced a range expansion around 0.31 Mya. Populations with high genetic and haplotype diversity were found on the QTP platform as well in the Hengduan Mountains. The ecological niche modeling results showed that there were suitable habitats on both the QTP platform and in the Hengduan Mountains during the LGM. CONCLUSION: Our results support a scenario that both nunataks and the massif de refuge hypotheses could explain the distribution of R. crenulata. We also confirmed that Quaternary climatic oscillations could promote plant speciation in some circumstances. This study adds to a growing body of evidence suggesting that the QTP plant lineages exhibited diverse reactions to the Quaternary climatic oscillations.

Climate Is Not All: Evidence From Phylogeography of Rhodiola fastigiata (Crassulaceae) and Comparison to Its Closest Relatives.

How geological events and climate oscillations in the Pleistocene glaciation shaped the geographic distribution of genetic variation of species on the Qinghai-Tibetan Plateau (QTP) and its adjacent areas has been extensively studied. However, little studies have investigated whether closely related species in the same genus with similar physiological and life history traits responded similarly to the glacial climatic oscillations. If this is not the case, we would expect that the population histories of studied species were not driven by extrinsic environmental changes alone. Here we conducted a phylogeographic study of a succulent alpine plant Rhodiola fastigiata, using sequences from chloroplast genome and nrITS region, as well as ecological niche modeling. The results of R. fastigiata were compared to other congeneric species that have been studied, especially to R. alsia and R. crenulata. We found that for both markers, two geographic groups could be revealed, corresponding to the QTP plateau and the Hengduan Mountains, respectively, indicating isolated refugia in those two areas. The two groups diverged 1.23 Mya during the Pleistocene. We detected no significant population expansion by mismatch distribution analysis and Bayesian Skyline Plot. We found that even these similar species with similar physiological and life history traits have had different demographic histories in the Quaternary glacial periods. Our comparative phylogeographic study sheds new lights into phylogeographic research that extrinsic environmental changes are not the only factor that can drive population demography, and other factors, such as coevolved interactions between plants and their specialized pathogens, that probably played a role need to be examined with more case studies.

Author Correction: Establishment of the most comprehensive ITS2 barcode database to date of the traditional medicinal plant Rhodiola (Crassulaceae).

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Establishment of the most comprehensive ITS2 barcode database to date of the traditional medicinal plant Rhodiola (Crassulacaee).

The roots and rhizomes of Rhodiola crenulata and R. rosea have been used worldwide as adaptogens for hundreds of years. However, rapid growth in demand has resulted in merchants using other species of Rhodiola as adulterants. Here, we surveyed 518 individuals representing 47 of the 55 species in the genus, including 253 R. crenulata individuals from 16 populations and 98 R. rosea individuals from 11 populations, to evaluate the utility of the internal transcribed spacer 2 (ITS2) barcode for identification of Rhodiola species. We detected six haplotypes in R. crenulata and only one haplotype in R. rosea. An obvious overlap between intra- and inter-specific distance was detected, and the authentication efficacy of ITS2, which was assessed by BLAST1, a nearest distance method, and a tree test, was much lower than in other groups. However, R. crenulata and R. rosea could be exactly identified. Analysis showed that the secondary structure of ITS2 differs in R. crenulata and its closest relatives. Our results demonstrated that both a mini barcode from ITS2 and the structure of ITS2 are effective markers for the identification of R. crenulata and R. rosea. This study represents the most comprehensive database of ITS2 barcodes in Rhodiola to date and will be useful in Rhodiola species identification.