SUMOylation of DISC1: a potential role in neural progenitor proliferation in the developing cortex

DISC1 is a multifunctional, intracellular scaffold protein. At the cellular level, DISC1 plays a pivotal role in neural progenitor proliferation, migration, and synaptic maturation. Perturbation of the biological pathways involving DISC1 is known to lead to behavioral changes in rodents, which supports a clinical report of a Scottish pedigree in which the majority of family members with disruption of the DISC1 gene manifest depression, schizophrenia, and related mental conditions. The discrepancy between modest evidence in genetics and strong biological support for the role of DISC1 in mental conditions suggests a working hypothesis that regulation of DISC1 at the protein level, such as posttranslational modification, may play a role in the pathology of mental conditions. In this study, we report on the SUMOylation of DISC1. This posttranslational modification occurs on lysine residues where the small ubiquitin-related modifier (SUMO) and its homologs are conjugated to a large number of cellular proteins, which in turn regulates their subcellular distribution and protein stability. By using in silico, biochemical, and cell-biological approaches, we now demonstrate that human DISC1 is SUMOylated at one specific lysine 643 (K643). We also show that this residue is crucial for proper neural progenitor proliferation in the developing cortex

Alterations of the human gut microbiome in multiple sclerosis

The gut microbiome plays an important role in immune function and has been implicated in several autoimmune disorders. Here we use 16S rRNA sequencing to investigate the gut microbiome in subjects with multiple sclerosis (MS, n=60) and healthy controls (n=43). Microbiome alterations in MS include increases in Methanobrevibacter and Akkermansia and decreases in Butyricimonas, and correlate with variations in the expression of genes involved in dendritic cell maturation, interferon signalling and NF-kB signalling pathways in circulating T cells and monocytes. Patients on disease-modifying treatment show increased abundances of Prevotella and Sutterella, and decreased Sarcina, compared with untreated patients. MS patients of a second cohort show elevated breath methane compared with controls, consistent with our observation of increased gut Methanobrevibacter in MS in the first cohort. Further study is required to assess whether the observed alterations in the gut microbiome play a role in, or are a consequence of, MS pathogenesis

Nitrate reductase and growth of Arabidopsis thaliana in solution culture

Abstract As a principal limiting nutrient, the metabolism of nitrogen is central to understanding plant growth and performance. Nitrate reductase (NR) is the first, and thus a critical, enzyme in the overall pathway for N incorporation. As such, and because it is highly regulated at the transcriptional, translational and post-translational levels, NR has received a large amount of experimental attention. On the other hand, there have been a number of reports that plant growth can be maintained with much less, or much more, NR activity than is normally present, and without the normal controls. The actual relationship between NR activity and growth is, however, poorly understood. The objective of this study was to examine the integration of growth, protein accumulation and patterns of nitrate reductase (NR) activity in wild-type Arabidopsis thaliana L. plants and a mutant lacking NR. Our results show that WT plants, during their exponential growth phase, had as much as 15-times more NR activity than needed to support the recorded growth. NR-deficient mutants, on the other hand, achieved equivalent exponential growth rates, lagging WT by about two weeks, but had less than 20% of the NR needed to support that growth. Both WT and mutants grew equally well when nitrite was supplied instead of nitrate, so long as the nitrite was continuously present, suggesting involvement of N-conversions in the growth medium. When N was supplied only in short pulses, nitrite toxicity was indicated, but the mutants still survived and grew on nitrate. We conclude that the absolute requirements for NR in plants may be highly flexible. The mechanism by which NR-deficient plants incorporate nitrate and support growth remains unclear, however

T cell responses to COVID-19 infection and vaccination in patients with multiple sclerosis receiving disease-modifying therapy

Background: Multiple sclerosis (MS) is a neurological disorder marked by accumulating immune-mediated damage to the central nervous system. The dysregulated immune system in MS combined with immune effects of disease-modifying therapies (DMTs) used in MS treatment could alter responses to infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). Most of the literature on immune response to SARS-CoV-2 infection and COVID-19 vaccination, in both the general population and patients with MS on DMTs, has focused on humoral immunity. However, immune response to COVID-19 involves multiple lines of defense, including T cells. Objective and Methods: We review innate and adaptive immunity to COVID-19 and expand on the role of T cells in mediating protective immunity against SARS-CoV-2 infection and in responses to COVID-19 vaccination in MS. Results: Innate, humoral, and T cell immune responses combat COVID-19 and generate protective immunity. Assays detecting cytokine expression by T cells show an association between SARS-CoV-2-specific T cell responses and milder/asymptomatic COVID-19 and protective immune memory. Conclusion: Studies of COVID-19 immunity in people with MS on DMTs should ideally include comprehensive assessment of innate, humoral, and T cell responses.</p

A probiotic modulates the microbiome and immunity in multiple sclerosis

Objective: Effect of a probiotic on the gut microbiome and peripheral immune function in healthy controls and relapsing-remitting multiple sclerosis (MS) patients. Methods: MS patients (N = 9) and controls (N = 13) were orally administered a probiotic containing Lactobacillus, Bifidobacterium, and Streptococcus twice-daily for two months. Blood and stool specimens were collected at baseline, after completion of the 2-month treatment, and 3 months after discontinuation of therapy. Frozen peripheral blood mononuclear cells (PBMCs) were used for immune cell profiling. Stool samples were used for 16S rRNA profiling and metabolomics. Results: Probiotic administration increased the abundance of several taxa known to be depleted in MS such as Lactobacillus. We found that probiotic use decreased the abundance of taxa previously associated with dysbiosis in MS, including Akkermansia and Blautia. Predictive metagenomic analysis revealed a decrease in the abundance of several KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways associated with altered gut microbiota function in MS patients, such as methane metabolism, following probiotic supplementation. At the immune level, probiotic administration induced an anti-inflammatory peripheral immune response characterized by decreased frequency of inflammatory monocytes, decreased mean fluorescence intensity (MFI) of CD80 on classical monocytes, as well as decreased human leukocyte antigen (HLA) D related MFI on dendritic cells. Probiotic administration was also associated with decreased expression of MS risk allele HLA-DQA1 in controls. Probiotic-induced increase in abundance of Lactobacillus and Bifidobacterium was associated with decreased expression of MS risk allele HLA.DPB1 in controls. Interpretation: Our results suggest that probiotics could have a synergistic effect with current MS therapies. Ann Neurol 2018