Transgenic Monkey Model of the Polyglutamine Diseases Recapitulating Progressive Neurological Symptoms

Age-associated neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and the polyglutamine (polyQ) diseases, are becoming prevalent as a consequence of elongation of the human lifespan. Although various rodent models have been developed to study and overcome these diseases, they have limitations in their translational research utility owing to differences from humans in brain structure and function and in drug metabolism. Here, we generated a transgenic marmoset model of the polyQ diseases, showing progressive neurological symptoms including motor impairment. Seven transgenic marmosets were produced by lentiviral introduction of the human ataxin 3 gene with 120 CAG repeats encoding an expanded polyQ stretch. Although all offspring showed no neurological symptoms at birth, three marmosets with higher transgene expression developed neurological symptoms of varying degrees at 3–4 months after birth, followed by gradual decreases in body weight gain, spontaneous activity, and grip strength, indicating time-dependent disease progression. Pathological examinations revealed neurodegeneration and intranuclear polyQ protein inclusions accompanied by gliosis, which recapitulate the neuropathological features of polyQ disease patients. Consistent with neuronal loss in the cerebellum, brain MRI analyses in one living symptomatic marmoset detected enlargement of the fourth ventricle, which suggests cerebellar atrophy. Notably, successful germline transgene transmission was confirmed in the second-generation offspring derived from the symptomatic transgenic marmoset gamete. Because the accumulation of abnormal proteins is a shared pathomechanism among various neurodegenerative diseases, we suggest that this new marmoset model will contribute toward elucidating the pathomechanisms of and developing clinically applicable therapies for neurodegenerative diseases.ArticleeNeuro.4(2):e0250(2017)journal articl

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

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

Clinical Significance of COVID-19 and Diabetes: In the Pandemic Situation of SARS-CoV-2 Variants including Omicron (B.1.1.529)

The coronavirus disease 2019 (COVID-19) global pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains uncontrolled, with the spread of emerging variants. According to accumulating evidence, diabetes is one of the leading risk factors for a severe COVID-19 clinical course, depending on the glycemic state before admission and during COVID-19 hospitalization. Multiple factors are thought to be responsible, including an altered immune response, coexisting comorbidity, and disruption of the renin-angiotensin system through the virus–host interaction. However, the precise underlying mechanisms remain under investigation. Alternatively, the focus is currently on the diabetogenic and ketosis-prone potential of SARS-CoV-2 itself, even for probable triggers of stress and steroid-induced hyperglycemia in COVID-19. In this article, we present a comprehensive review of the recent literature on the clinical and experimental findings associated with diabetes and COVID-19, and we discuss their bidirectional relationship, i.e., the risk for an adverse prognosis and the deleterious effects on glycometabolism. Accurate assessments of the incidence of new-onset diabetes induced by COVID-19 and its pathogenicity are still unknown, especially in the context of the circulation of SARS-CoV-2 variants, such as Omicron (B.1.1.529), which is a major challenge for the future

Achievement of sufficient antibody response after a fourth dose of wild‐type SARS‐CoV‐2 mRNA vaccine in nursing home residents

Abstract Background Infection control during COVID‐19 outbreaks in nursing facilities is a critical public health issue. Antibody responses before and after the fourth (second booster) dose of wild‐type severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccine in nursing home residents have not been fully characterized. Methods This study included 112 individuals: 54 nursing home residents (mean age: 84.4 years; 35 SARS‐CoV‐2‐naive and 19 previously infected) and 58 healthcare workers (mean age: 47.7 years; 25 SARS‐CoV‐2‐naive and 33 previously infected). Antispike and antinucleocapsid antibody responses to messenger RNA vaccination were evaluated using serum samples collected shortly and 5 months after the third dose, and shortly after the fourth dose. Results The median immunoglobulin G (IgG) level in SARS‐CoV‐2‐naive residents was similar to that in SARS‐CoV‐2‐naive healthcare workers after the fourth dose (24,026.3 vs. 30,328.6 AU/mL, p = .79), whereas after the third dose the IgG level of SARS‐CoV‐2‐naive residents was approximately twofold lower than that in SARS‐CoV‐2‐naive healthcare workers. In residents with previous SARS‐CoV‐2 infection, timing of infection in relation to vaccination affected the kinetics of antibody responses. Residents infected after the third dose showed the highest IgG levels after the fourth dose among all groups (median: 64,328.8 AU/mL), in contrast to residents infected before initiating vaccination with antibody levels similar to those of SARS‐CoV‐2‐naive residents. Conclusions Advanced aged nursing home residents, poor responders in the initial SARS‐CoV‐2 vaccine series, could achieve sufficient antibody responses after the fourth (second booster) vaccination, comparable to those of younger adults

Transgenic Monkey Model of the Polyglutamine Diseases Recapitulating Progressive Neurological Symptoms

Age-associated neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and the polyglutamine (polyQ) diseases, are becoming prevalent as a consequence of elongation of the human lifespan. Although various rodent models have been developed to study and overcome these diseases, they have limitations in their translational research utility owing to differences from humans in brain structure and function and in drug metabolism. Here, we generated a transgenic marmoset model of the polyQ diseases, showing progressive neurological symptoms including motor impairment. Seven transgenic marmosets were produced by lentiviral introduction of the human ataxin 3 gene with 120 CAG repeats encoding an expanded polyQ stretch. Although all offspring showed no neurological symptoms at birth, three marmosets with higher transgene expression developed neurological symptoms of varying degrees at 3–4 months after birth, followed by gradual decreases in body weight gain, spontaneous activity, and grip strength, indicating time-dependent disease progression. Pathological examinations revealed neurodegeneration and intranuclear polyQ protein inclusions accompanied by gliosis, which recapitulate the neuropathological features of polyQ disease patients. Consistent with neuronal loss in the cerebellum, brain MRI analyses in one living symptomatic marmoset detected enlargement of the fourth ventricle, which suggests cerebellar atrophy. Notably, successful germline transgene transmission was confirmed in the second-generation offspring derived from the symptomatic transgenic marmoset gamete. Because the accumulation of abnormal proteins is a shared pathomechanism among various neurodegenerative diseases, we suggest that this new marmoset model will contribute toward elucidating the pathomechanisms of and developing clinically applicable therapies for neurodegenerative diseases