Survival motor neuron (SMN) protein in the spinal anterior horn cells of patients with sporadic amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving mainly the upper and lower motor neurons of adult humans. With regard to the pathomechanism of spinal anterior horn cell (AHC) degeneration in ALS, copy number abnormalities of the survival motor neuron (SMN) genes have been reported in sporadic (s) ALS. SMN protein is the protein responsible for the pathogenesis of spinal muscular atrophy (SMA), an autosomal recessive disease characterized by lower motor neuron loss and muscle atrophy. The disease is caused by deficiency of SMN protein induced by mutation of one of the SMA-associated genes, SMN1. To clarify the role of SMN protein in the degeneration of spinal AHCs in sALS, we examined the amount of cytoplasmic SMN protein in individual AHCs using cytofluorophotometry in 9 patients with sALS and 10 control subjects. It was found that: 1) SMN protein was present in the cytoplasm, nucleus and nucleolus of AHCs and in the nucleus of glial cells, 2) expression of SMN protein in AHCs was significantly associated with cell size in both sALS patients and controls, 3) expression of SMN protein per unit area in AHCs was similar in sALS patients and controls. These findings suggest that: 1) the amount of SMN protein in the cytoplasm of AHCs is strictly controlled in accordance with cell size, in both sALS patients and controls, 2) the amount of SMN protein in the AHCs of sALS patients may be reduced when the AHCs are atrophic, and 3) decrease of SMN protein in the AHCs of sALS patients may be a secondary, and not primary, phenomenon according to their sizes.ArticleBRAIN RESEARCH. 1372:152-159 (2011)journal articl

Cell-Surface Protein Profiling Identifies Distinctive Markers of Progenitor Cells in Human Skeletal Muscle

SummarySkeletal muscle contains two distinct stem/progenitor populations. One is the satellite cell, which acts as a muscle stem cell, and the other is the mesenchymal progenitor, which contributes to muscle pathogeneses such as fat infiltration and fibrosis. Detailed and accurate characterization of these progenitors in humans remains elusive. Here, we performed comprehensive cell-surface protein profiling of the two progenitor populations residing in human skeletal muscle and identified three previously unrecognized markers: CD82 and CD318 for satellite cells and CD201 for mesenchymal progenitors. These markers distinguish myogenic and mesenchymal progenitors, and enable efficient isolation of the two types of progenitors. Functional study revealed that CD82 ensures expansion and preservation of myogenic progenitors by suppressing excessive differentiation, and CD201 signaling favors adipogenesis of mesenchymal progenitors. Thus, cell-surface proteins identified here are not only useful markers but also functionally important molecules, and provide valuable insight into human muscle biology and diseases

Repurposing bromocriptine for Aβ metabolism in Alzheimer’s disease (REBRAnD) study : randomised placebo-controlled double-blind comparative trial and open-label extension trial to investigate the safety and efficacy of bromocriptine in Alzheimer’s disease with presenilin 1 (PSEN1) mutations

Introduction Alzheimer’s disease (AD) is one of the most common causes of dementia. Pathogenic variants in the presenilin 1 (PSEN1) gene are the most frequent cause of early-onset AD. Medications for patients with AD bearing PSEN1 mutation (PSEN1-AD) are limited to symptomatic therapies and no established radical treatments are available. Induced pluripotent stem cell (iPSC)-based drug repurposing identified bromocriptine as a therapeutic candidate for PSEN1-AD. In this study, we used an enrichment strategy with iPSCs to select the study population, and we will investigate the safety and efficacy of an orally administered dose of bromocriptine in patients with PSEN1-AD. Methods and analysis This is a multicentre, randomised, placebo-controlled trial. AD patients with PSEN1 mutations and a Mini Mental State Examination-Japanese score of ≤25 will be randomly assigned, at a 2:1 ratio, to the trial drug or placebo group (≥4 patients in TW-012R and ≥2 patients in placebo). This clinical trial consists of a screening period, double-blind phase (9 months) and extension phase (3 months). The double-blind phase for evaluating the efficacy and safety is composed of the low-dose maintenance period (10 mg/day), high-dose maintenance period (22.5 mg/day) and tapering period of the trial drug. Additionally, there is an open-labelled active drug extension period for evaluating long-term safety. Primary outcomes are safety and efficacy in cognitive and psychological function. Also, exploratory investigations for the efficacy of bromocriptine by neurological scores and biomarkers will be conducted. Ethics and dissemination The proposed trial is conducted according to the Declaration of Helsinki, and was approved by the Institutional Review Board (K070). The study results are expected to be disseminated at international or national conferences and published in international journals following the peer-review process

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Improved near-infrared sensitivity of a back-side illuminated image sensor with a metal reflector

To improve the near-infrared sensitivity of an image sensor that has a conventional pixel structure, we made use of the metal wiring layer as a reflector in addition to the method of back-side illumination from the etched back surface of the sensor. We f

FAB/MSによる食用キノコに含まれる糖脂質の構造特性

[Synopsis] The structures of glycolipids isolated from mushrooms, Hypsizigus marmoreus (Bunashimeji) and Pleurotus citrinopileatus (Nireouma) were determined to be (4E,8E)-N-2-hydroxyhexadecanoyl-1-O-β-glucopyranosyl-9-methyl-C_-sphinga-4,8-dienine (1), phosphodihexose N-(2-hydroxyoctadecanoyl)-4-hydroxy-C_-sphinganine (2), phosphodihexose N-(2-hydroxyhexadecanoyl)-4-hydroxy-C_-sphinganine (3), phosphodihexose N-(2-hydroxytetracosanoy1)-4-hydroxy-C_-sphinganine (4), and phosphodihexose N-(2-hydroxydocosanoy1)-4-hydroxy-C_-sphinganine (5). In particular, location of the double bonds in the long-chain base of 1 was clearly determined by the B/E constant linked scan method. The structure of cerebroside having a long-chain base of 9-methyl-C_-sphinga-4,8-dienine could be determined in general by the presence of characteristic fragment ions of [C_-sphingadienine + H-H_2O]^+at m/z 276 and [C_-sphingadienine + H]^+ at m/z 294, and the fatty acid carbon number could be calculated from the characteristic fragment ion of [ceramide - 180]^+ ([MH - GlcOH - 180]^+) in positive ion mode FAB mass spectrometry. In the structural determination of 2-5, the ions of m/z 421 and 720 in the negative ion mode analyses are assigned to be characteristic peaks of phosphodihexose and phytosphingosine containing phosphodihexose, respectively. This method proved to be useful for the structural determination of unstable natural products such as lipids. 　（摘要）　機能性天然物分子探索の一環として、食用キノコに含まれる糖脂質の構造解析について研究を行っている。本稿では、ブナシメジ (Hypsizigus marmoreus) および楡黄麻 (Pleurotus citrinopileatus) から得た糖脂質のFAB/MSの構造特性について紹介する。得られた糖脂質の構造は、(4E, 8E)-N-2-hydroxyhexadecanoyl-1-O-β-glucopyranosyl-9-methyl-C_-sphinga-4,8-dienine (1), phosphodihexose N-(2-hydroxyoctadecanoyl)-4-hydroxy-C_-sphinganine (2), phosphodihexose N-(2-hydroxyhexadecanoyl)-4-hydroxy-C_-sphinganine(3), phosphodihexose N-(2-hydroxytetracosanoyl)-4-hydroxy-C_-sphinganine (4) および phosphodihexose N-(2-hydroxydocosanoyl)-4-hydroxy-C_-sphinganine (5) と決定した。特に、これらの構造特性において、長鎖アルキルの不飽和結合の位置、極性部および脂肪酸の種類はB/E一定リンクドスキャン法を用いたFAB/MSを測定することにより容易に決定された