Oxidative stress as a candidate mechanism for accelerated neuroectodermal differentiation due to trisomy 21

Down syndrome (DS), also known as trisomy 21, is the most frequent genetic cause of intellectual disability. Although the mechanism remains unknown, delayed brain development is assumed to be involved in DS intellectual disability. Analyses with human with DS and mouse models have shown that defects in embryonic cortical neurogenesis may lead to delayed brain development. Cre-loxP-mediated chromosomal engineering has allowed the generation of a variety of mouse models carrying various partial Mmu16 segments. These mouse models are useful for determining genotype-phenotype correlations and identifying dosage-sensitive genes involved in the impaired neurogenesis. In this review, we summarize several candidate genes and pathways that have been linked to defective cortical neurogenesis in DS.

Genes Associated with Disturbed Cerebral Neurogenesis in the Embryonic Brain of Mouse Models of Down Syndrome.

Down syndrome (DS), also known as trisomy 21, is a genetic disorder caused by triplication of Chromosome 21. Gene triplication may compromise different body functions but invariably impairs intellectual abilities starting from infancy. Moreover, after the fourth decade of life people with DS are likely to develop Alzheimer’s disease. Neurogenesis impairment during fetal life stages and dendritic pathology emerging in early infancy are thought to be key determinants of alterations in brain functioning in DS. Although the progressive improvement in medical care has led to a notable increase in life expectancy for people with DS, there are currently no treatments for intellectual disability. Increasing evidence in mouse models of DS reveals that pharmacological interventions in the embryonic and neonatal periods may greatly benefit brain development and cognitive performance. The most striking results have been obtained with pharmacotherapies during embryonic life stages, indicating that it is possible to pharmacologically rescue the severe neurodevelopmental defects linked to the trisomic condition. These findings provide hope that similar benefits may be possible for people with DS. This review summarizes current knowledge regarding (i) the scope and timeline of neurogenesis (and dendritic) alterations in DS, in order to delineate suitable windows for treatment; (ii) the role of triplicated genes that are most likely to be the key determinants of these alterations, in order to highlight possible therapeutic targets; and (iii) prenatal and neonatal treatments that have proved to be effective in mouse models, in order to rationalize the choice of treatment for human application. Based on this body of evidence we will discuss prospects and challenges for fetal therapy in individuals with DS as a potential means of drastically counteracting the deleterious effects of gene triplication.

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The Challenging Pathway of Treatment for Neurogenesis Impairment in Down Syndrome: Achievements and Perspectives

Abstract Reading Disability (RD) is often characterized by difficulties in the phonology of the language. While the molecular mechanisms underlying it are largely undetermined, loci are being revealed by genome-wide association studies (GWAS). In a previous GWAS for word reading (Price, 2020), we observed that top single-nucleotide polymorphisms (SNPs) were located near to or in genes involved in neuronal migration/axon guidance (NM/AG) or loci implicated in autism spectrum disorder (ASD). A prominent theory of RD etiology posits that it involves disturbed neuronal migration, while potential links between RD-ASD have not been extensively investigated. To improve power to identify associated loci, we up-weighted variants involved in NM/AG or ASD, separately, and performed a new Hypothesis-Driven (HD)–GWAS. The approach was applied to a Toronto RD sample and a meta-analysis of the GenLang Consortium. For the Toronto sample ( n = 624), no SNPs reached significance; however, by gene-set analysis, the joint contribution of ASD-related genes passed the threshold ( p ~1.45 × 10 –2 , threshold = 2.5 × 10 –2 ). For the GenLang Cohort ( n = 26,558), SNPs in DOCK7 and CDH4 showed significant association for the NM/AG hypothesis (sFDR q = 1.02 × 10 –2 ). To make the GenLang dataset more similar to Toronto, we repeated the analysis restricting to samples selected for reading/language deficits ( n = 4152). In this GenLang selected subset, we found significant association for a locus intergenic between BTG3 - C21orf91 for both hypotheses (sFDR q &lt; 9.00 × 10 –4 ). This study contributes candidate loci to the genetics of word reading. Data also suggest that, although different variants may be involved, alleles implicated in ASD risk may be found in the same genes as those implicated in word reading. This finding is limited to the Toronto sample suggesting that ascertainment influences genetic associations. 

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Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities

Down syndrome (DS) is the most common genetic cause of intellectual disability with a wide spectrum of neurodevelopmental outcomes. Magnetic resonance imaging (MRI) has been used to investigate differences in whole and/or regional brain volumes in DS from infancy to adulthood. However, to date, there have been relatively few in vivo neonatal brain imaging studies in DS, despite the presence of clearly identifiable characteristics at birth. Improved understanding of early brain development in DS is needed to assess phenotypic severity and identify appropriate time windows for early intervention. In this study, we used in vivo brain MRI to conduct a comprehensive volumetric phenotyping of the neonatal brain in DS. Using a robust cross-sectional reference sample of close to 500 preterm- to term-born control neonates, we have performed normative modelling and quantified volumetric deviation from the normative mean in 25 individual infants with DS [postmenstrual age at scan, median (range) = 40.57 (32.43 – 45.57) weeks], corrected for sex, age at scan and age from birth. We found that absolute whole brain volume was significantly reduced in neonates with DS (pFDR <0.0001), as were most underlying absolute tissue volumes, except for the lentiform nuclei and the extracerebral cerebrospinal fluid (eCSF), which were not significantly different, and the lateral ventricles, which were significantly enlarged (pFDR <0.0001). Relative volumes, adjusting for underlying differences in whole brain volume, revealed a dynamic shift in brain proportions in neonates with DS. In particular, the cerebellum, as well as the cingulate, frontal, insular and occipital white matter (WM) segments were significantly reduced in proportion (pFDR <0.0001). Conversely, deep grey matter (GM) structures, such as the thalami and lentiform nuclei, as well as CSF-filled compartments, such as the eCSF and the lateral ventricles were significantly enlarged in proportion (pFDR <0.0001). We also observed proportionally reduced frontal and occipital lobar volumes, in contrast with proportionally enlarged temporal and parietal lobar volumes. Lastly, we noted age-related volumetric differences between neonates with and without a congenital heart defect (CHD), indicating that there may be a baseline brain phenotype in neonates with DS, which is further altered in the presence of CHD. In summary, we provide a comprehensive volumetric phenotyping of the neonatal brain in DS and observe many features that appear to follow a developmental continuum, as noted in older age cohorts. There are currently no paediatric longitudinal neuroimaging investigations in DS, starting from the earliest time points, which greatly impedes our understanding of the developmental continuum of neuroanatomical parameters in DS. Whilst life expectancy of individuals with DS has greatly improved over the last few decades, early interventions may be essential to help improve outcomes and quality of life. GRAPHICAL ABSTRACT

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Comprehensive volumetric phenotyping of the neonatal brain in Down syndrome

Neuropathological diseases of the central nervous system (CNS) are frequently associated with impaired differentiation of the oligodendroglial cell lineage and subsequent alterations in white matter structure and dynamics. Down syndrome (DS), or trisomy 21, is the most common genetic cause for cognitive impairments and intellectual disability (ID) and is associated with a reduction in the number of neurons and oligodendrocytes, as well as with hypomyelination and astrogliosis. Recent studies mainly focused on neuronal development in DS and underestimated the role of glial cells as pathogenic players. This also relates to C21ORF91, a protein considered a key modulator of aberrant CNS development in DS. We investigated the role of C21orf91 ortholog in terms of oligodendrogenesis and myelination using database information as well as through cultured primary oligodendroglial precursor cells (OPCs). Upon modulation of C21orf91 gene expression, we found this factor to be important for accurate oligodendroglial differentiation, influencing their capacity to mature and to myelinate axons. Interestingly, C21orf91 overexpression initiates a cell population coexpressing astroglial- and oligodendroglial markers indicating that elevated C21orf91 expression levels induce a gliogenic shift towards the astrocytic lineage reflecting non-equilibrated glial cell populations in DS brains.

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Jana Schütte

Papers

C21orf91 Regulates Oligodendroglial Precursor Cell Fate-A Switch in the Glial Lineage?