Oligodendroglia heterogeneity in the human central nervous system

It is the centenary of the discovery of oligodendrocytes and we are increasingly aware of their importance in the functioning of the brain in development, adult learning, normal ageing and in disease across the life course, even in those diseases classically thought of as neuronal. This has sparked more interest in oligodendroglia for potential therapeutics for many neurodegenerative/neurodevelopmental diseases due to their more tractable nature as a renewable cell in the central nervous system. However, oligodendroglia are not all the same. Even from the first description, differences in morphology were described between the cells. With advancing techniques to describe these differences in human tissue, the complexity of oligodendroglia is being discovered, indicating apparent functional differences which may be of critical importance in determining vulnerability and response to disease, and targeting of potential therapeutics. It is timely to review the progress we have made in discovering and understanding oligodendroglial heterogeneity in health and neuropathology.

Gene Expression of Diverse Cryptococcus Isolates during Infection of the Human Central Nervous System

Cryptococcus is the most common fungus causing high-morbidity and -mortality human meningitis. This encapsulated yeast has a unique propensity to travel to the central nervous system to produce disease.

Short-Term High-Fat Diet Promotes Increased Lysine Crotonylation in Cerebral Cortex

Protein lysine crotonylation is a newly discovered protein post-translational modification (PTM), which has been associated with cellular metabolism, cell cycle, gene transcription, DNA damage response. However, its potential roles related to human central nervous system diseases remain largely unknown. In the present study, we observed a significant elevated lysine crotonylation in a screening of nine lysine acylations in cortex tissues of HFD-fed mice after short-term overfeeding. On the base of previous reports and molecular weight of proteins, we also speculate that actin, ERK2 or GAPDH and CDK1 might be modified by lysine crotonylation (KCr). Taken together, our findings highlight a potential role of protein lysine crotonylation in HFD-induced brain disorders and as possible therapeutic candidates in the future.

Nos2-/- mice infected with M. tuberculosis develop neurobehavioral changes and immunopathology mimicking human central nervous system tuberculosis

Understanding the pathophysiology of central nervous system tuberculosis (CNS-TB) is hampered by the lack of a good pre-clinical model that mirrors the human CNS-TB infection. We developed a murine CNS-TB model that demonstrates neurobehavioral changes with similar immunopathology with human CNS-TB. Intra-cerebroventricular (i.c.vent.) infection of Nos2-/- mice with Mycobacterium tuberculosis (M.tb) led to development of neurological signs and more severe brain granulomas compared to C3HeB/FeJ mice. Compared with CDC1551 M.tb, H37Rv M.tb infection resulted in a higher neurobehavioral score and earlier mortality. I.c.vent. infection caused necrotic neutrophil-dominated pyogranulomas in the brain relative to intravenous (i.v.) infection which resulted in disseminated granulomas and mycobacteraemia. Immunological analysis found H37Rv i.c.vent.-infected mice to demonstrate higher brain concentrations of inflammatory cytokines, chemokines and adhesion molecule ICAM-1 than H37Rv i.v.-infected mice. Our murine CNS-TB model serves as a pre-clinical platform to dissect host-pathogen interactions and evaluate therapeutic agents for CNS-TB.

Developmental landscape of human forebrain at a single-cell level unveils early waves of oligodendrogenesis

Oligodendrogenesis in the human central nervous system has been mainly observed at the second trimester of gestation, a much later developmental stage compared to mouse. Here we characterize the transcriptomic neural diversity in the human forebrain at post conceptual weeks (PCW) 8 to 10, using single-cell RNA-Seq. We find evidence of the emergence of a first wave of oligodendrocyte lineage cells as early as PCW 8, which we also confirm at the epigenomic level with single-cell ATAC-Seq. Using regulatory network inference, we predict key transcriptional events leading to the specification of oligodendrocyte precursor cells (OPCs). Moreover, by profiling the spatial expression of fifty key genes using In Situ Sequencing (ISS), we identify regions in the human ventral fetal forebrain where oligodendrogenesis first occurs. Our results indicate evolutionary conservation of the first wave of oligodendrogenesis between mouse and human and describe regulatory mechanisms required for human OPC specification.

Proteomics of Multiple Sclerosis: Inherent Issues in Defining the Pathoetiology and Identifying (Early) Biomarkers

Multiple Sclerosis (MS) is a demyelinating disease of the human central nervous system having an unconfirmed pathoetiology. Although animal models are used to mimic the pathology and clinical symptoms, no single model successfully replicates the full complexity of MS from its initial clinical identification through disease progression. Most importantly, a lack of preclinical biomarkers is hampering the earliest possible diagnosis and treatment. Notably, the development of rationally targeted therapeutics enabling pre-emptive treatment to halt the disease is also delayed without such biomarkers. Using literature mining and bioinformatic analyses, this review assessed the available proteomic studies of MS patients and animal models to discern (1) whether the models effectively mimic MS; and (2) whether reasonable biomarker candidates have been identified. The implication and necessity of assessing proteoforms and the critical importance of this to identifying rational biomarkers are discussed. Moreover, the challenges of using different proteomic analytical approaches and biological samples are also addressed.