Biology subjects

O'Dea, M. R.

Publications and source records attributed to O'Dea, M. R..

3 recordsLinked to original sources

bioRxiv2025

Myelin pathology is a key feature of X-linked Dystonia Parkinsonism

X-linked Dystonia-Parkinsonism (XDP) is a progressive, adult-onset neurodegenerative movement disorder that predominantly affects males of Filipino descent1-3. The disease is caused by the insertion of a SINE-VNTR-Alu subfamily F (SVA_F) retrotransposon within an intron of the TATA-box binding protein-associated factor 1 (TAF1) gene4. A major barrier to understanding the pathophysiology of XDP has been the lack of relevant animal models. Here, we introduce a novel conditional humanized XDP mouse model harboring a hybrid mouse-human Taf1/TAF1 gene (hyTAF1) containing the pathogenic SVA_F insertion. We activated the hyTAF1 in Nestin+ neural progenitor cells and found that the resulting XDP male mice recapitulate features of the human disease including severe motor impairment, striatal atrophy, and reactive gliosis. Transcriptomic, histological, and electron microscopy analysis revealed a dramatic reduction in oligodendrocyte lineage cells and widespread myelin disruption. Consistent with these findings, postmortem brain tissue from XDP patients revealed similar myelin pathology, including near-complete loss of myelin in parts of the medial prefrontal cortex. Together, these results identify oligodendrocyte dysfunction and myelin loss as previously unrecognized contributors to XDP pathogenesis, providing new mechanistic insight into this debilitating disorder.

neuroscience↗

bioRxiv2025

Epigenetic memory astrocytes are likely an artifact of immune cell contamination

Innate immune memory, in which prior immune stimuli can "train" certain immune cells to respond more aggressively to subsequent challenges, is crucial for immune system plasticity in disease. Lee et al. [1] recently described a similar kind of immune memory state in astrocytes which they termed "epigenetic memory astrocytes". The discovery of astrocytes with immune memory could have tremendous importance in understanding and treating neurological disease. However, the RNA-seq data and in vitro experiments presented by Lee et al. to claim astrocytes possess pro-inflammatory immune memory show signs of immune cell contamination. Further, astrocyte-specific knockout of Ep300, the purported epigenetic regulator of this memory, did not reduce expression of any memory astrocyte signature genes. The FIND-seq signature used to verify the presence of epigenetic memory astrocytes in experimental autoimmune encephalomyelitis (EAE) also shows signs of immune cell contamination, and the cells identified as memory astrocytes in previously published EAE single-cell RNA-seq data are misannotated macrophages. Lastly, we find the purported epigenetic memory astrocytes identified in single-nucleus RNA-seq data of multiple sclerosis (MS) tissue are an artifact of ambient RNA, low quality nuclei, and non-astrocyte contamination. We conclude that the epigenetic memory astrocyte signature is likely driven by immune cell contamination and the existence of astrocyte immunological memory is insufficiently evidenced. We caution that astrocyte transcriptomic, epigenomic, and functional assays must take care to exclude contamination by immune cells, especially when evaluating the potential of astrocytes to perform immunological functions.

neuroscience↗

bioRxiv2023

Single-cell analysis of the nervous system at small and large scales with instant partitions

Single-cell RNA sequencing is a new frontier across all biology, particularly in neuroscience. While powerful for answering numerous neuroscience questions, limitations in sample input size, and initial capital outlay can exclude some researchers from its application. Here, we tested a recently introduced method for scRNAseq across diverse scales and neuroscience experiments. We benchmarked against a major current scRNAseq technology and found that PIPseq performed similarly, in line with earlier benchmarking data. Across dozens of samples, PIPseq recovered many brain cell types at small and large scales (1,000-100,000 cells/sample) and was able to detect differentially expressed genes in an inflammation paradigm. Similarly, PIPseq could detect expected and new differentially expressed genes in a brain single cell suspension from a knockout mouse model; it could also detect rare, virally-la-belled cells following lentiviral targeting and gene knockdown. Finally, we used PIPseq to investigate gene expression in a nontraditional model species, the little skate (Leucoraja erinacea). In total, PIPSeq was able to detect single-cell gene expression changes across models and species, with an added benefit of large scale capture and sequencing of each sample.

neuroscience↗