Biology subjects

Yusof, N. A. B. M.

Publications and source records attributed to Yusof, N. A. B. M..

4 recordsLinked to original sources

bioRxiv2022

Widespread dysregulation of mRNA splicing implicates RNA processing in the development and progression of Huntington's disease

In Huntingtons disease (HD), a CAG repeat expansion mutation in the HTT gene drives a gain-of-function toxicity that disrupts mRNA processing. Although widespread dysregulation of gene splicing in the striatum has been shown in human HD post-mortem brain tissue, post-mortem analyses are likely confounded by cell type composition changes due to neuronal loss and astrogliosis in late stage HD. This limits the ability to identify dysregulation related to early pathogenesis. To study alternative splicing changes in early HD, we performed RNA-sequencing analysis in an established isogenic HD neuronal cell model. We report cell type-associated and CAG length-dependent splicing changes, and find an enrichment of RNA processing genes coupled with neuronal function-related genes showing mutant HTT-associated splicing changes. Comparison with post-mortem data also identified splicing events associated with early pathogenesis that persist to later stages of disease. In summary, our results highlight splicing dysregulation in RNA processing genes in early and late-stage HD, which may lead to disrupted neuronal function and neuropathology.

neuroscience↗

bioRxiv2020

Ermin deficiency as an inside-out model of inflammatory dysmyelination

Ermin is an actin-binding protein found almost exclusively in the central nervous system (CNS) as a component of myelin sheaths. Although Ermin has been predicted to play a role in the formation and stability of myelin sheaths, this has not been directly examined in vivo. Here we show that Ermin is essential for myelin sheath integrity and normal saltatory conduction. Loss of Ermin in mice caused de-compacted and fragmented myelin sheaths and led to slower conduction along with progressive neurological deficits. RNA sequencing of the corpus callosum, the largest white matter structure in the CNS, pointed to inflammatory activation in aged Ermin-deficient mice, which was corroborated by increased levels of microgliosis and astrogliosis. The inflammatory milieu and myelin abnormalities were further associated with increased susceptibility to immune-mediated demyelination insult in Ermin knockout mice. Supporting a possible role of Ermin deficiency in inflammatory white matter disorders, a rare inactivating mutation in the ERMN gene was identified in multiple sclerosis patients. Our findings demonstrate a critical role for Ermin in maintaining myelin integrity. Given its near exclusive expression in myelinating oligodendrocytes, Ermin deficiency represents a compelling "inside-out" model of inflammatory dysmyelination and may offer a new paradigm for the development of myelin stability-targeted therapies.

neuroscience↗

bioRxiv2019

Integrative analysis identifies key molecular signatures underlying neurodevelopmental deficits in Fragile X Syndrome

Fragile X syndrome (FXS) is an incurable neurodevelopmental disorder with no effective treatment. FXS is caused by epigenetic silencing of FMR1 and loss of FMRP expression. To investigate the consequences of FMRP deficiency in the context of human physiology, we established isogenic FMR1 knockout (FMR1KO) human embryonic stem cells (hESCs). Integrative analysis of the transcriptomic and proteomic profiles of hESC-derived FMRP-deficient neurons revealed several dysregulated pathways important for brain development including processes related to axon development, neurotransmission, and the cell cycle. We functionally validated alterations in a number of these pathways, showing abnormal neural rosette formation and increased neural progenitor cell proliferation in FMR1KO cells. We further demonstrated neurite outgrowth and branching deficits along with impaired electrophysiological network activity in FMRP-deficient neurons. Using isogenic FMR1KO hESC-derived neurons, we reveal key molecular signatures and neurodevelopmental abnormalities arising from loss of FMRP. We anticipate that the FMR1KO hESCs and the neuronal transcriptome and proteome datasets will provide a platform to delineate the pathophysiology of FXS in human neural cells.

neuroscience↗

bioRxiv2018

Manipulation of microbiota reveals altered myelination and white matter plasticity in a model of Huntington disease

Structural and molecular myelination deficits represent early pathological features of Huntington disease (HD). Recent evidence from germ-free (GF) animals suggests a role for microbiota-gut-brain bidirectional communication in the regulation of myelination. In this study, we aimed to investigate the impact of microbiota on myelin plasticity and oligodendroglial population dynamics in the mixed-sex BACHD mouse model of HD. Ultrastructural analysis of myelin in the corpus callosum revealed alterations of myelin thickness in BACHD GF compared to specific-pathogen free (SPF) mice, whereas no differences were observed between wild-type (WT) groups. In contrast, myelin compaction was altered in all groups when compared to WT SPF animals. Levels of myelin-related proteins were generally reduced, and the number of mature oligodendrocytes was decreased in the prefrontal cortex under GF compared to SPF conditions, regardless of genotype. Minor differences in commensal bacteria at the family and genera levels were found in the gut microbiota of BACHD and WT animals housed in standard living conditions. Our findings indicate complex effects of a germ-free status on myelin-related characteristics, and highlight the adaptive properties of myelination as a result of environmental manipulation.

neuroscience↗