Biology subjects

Coe, M.

Publications and source records attributed to Coe, M..

3 recordsLinked to original sources

bioRxiv2026

Inter-individual variation of cellular and gene-expression properties of the human striatum

The human brain varies from person to person in ways that shape behaviors and vulnerabilities, yet the cellular and molecular bases for inter-individual variation are largely unknown. Here we describe an analysis of cellular and gene-expression variation in four key structures of the striatum complex - the caudate, putamen, nucleus accumbens, and internal capsule - as well as the prefrontal cortex, from single-nucleus RNA-seq analysis of 3.9 million nuclei from 178 adult brain donors. We found that people with more astrocytes in any one brain region tended to have this property in all brain regions sampled; the same was true of striatal interneurons, microglia, and oligodendrocyte precursor cells (OPCs). OPCs showed attrition with age, declining in numbers by approximately 40% between age 30 and age 80 in both gray matter and white matter regions. We identified thousands of age-associated (but few sex-associated) variations in gene expression; the vast majority of these effects of age were cell-type-specific. Aging most strongly affected gene expression in projection neurons - especially striatal medium spiny neurons (MSNs/SPNs) - and had a much smaller effect on gene expression in interneurons. Individuals ages could be predicted to within about five years based on RNA-expression patterns from any of the striatal cell types. Common genetic variants detectably affected the expression levels of some ten thousand genes; the great majority of these effects were cell-type-specific. These data will provide a foundation for exploring natural inter-individual variation, aging, and tissue-based studies of human brain vulnerabilities.

neuroscience↗

bioRxiv2022

Mitochondria dysregulation contributes to secondary neurodegeneration progression post-contusion injury in human 3D in vitro triculture brain tissue model.

Traumatic Brain injury-induced disturbances in mitochondrial fission-and-fusion dynamics have been linked to the onset and propagation of neuroinflammation and neurodegeneration. However, cell-type-specific contributions and crosstalk between neurons, microglia, and astrocytes in mitochondria-driven neurodegeneration after brain injury remain undefined. We developed a human three-dimensional in vitro triculture tissue model of a contusion injury, composed of neurons, microglia, and astrocytes, and examined the contributions of mitochondrial dysregulation to neuroinflammation and progression of injury-induced neurodegeneration. Pharmacological studies presented here suggest that fragmented mitochondria released by microglia are a key contributor to secondary neuronal damage progression after contusion injury, a pathway that requires astrocyte-microglia crosstalk. Controlling mitochondrial dysfunction thus offers an exciting option for the development of therapies for TBI patients.

neuroscience↗

bioRxiv2019

Combined use of design of experiments and metabolic engineering for optimization of nogalamycin production

Nogalamycin is an anthracycline antibiotic produced from Streptomyces nogalater that exerts its mechanism of action via inhibition of topoisomerase I. Nogalamycin has a unique tetracyclic structure composed of a 7-O-glycosidically linked L-nogalose sugar and a C2-C5\"-linked L-nogalamine residue that forms an epoxyoxacin ring. Nogalamycin was originally developed as an anticancer agent in the 1970s, however, it exhibited dose-limiting cardiotoxicity. Shortly after the discovery of nogalamycin, the semi-synthetic analogue 7-O-methylnogarol, or menogaril, was synthesized and exhibited a mild improvement in cardiotoxicity and anticancer efficacy. Menogaril lacks the 7-O-L-nogalose moiety and functions as a topoisomerase II inhibitor, like most anthracyclines, however this agent still proved too toxic for clinical use. Our laboratory is developing a production platform for microbial synthesis of novel nogalamycin analogs useful for treatment of human cancers or as antibiotics. Our initial hypothesis is that overexpression of structural genes responsible for synthesis of TDP-deoxysugar and polyketide precursor substrates, respectively, will increase carbon flux towards nogalamycin production. In this study, we have employed metabolic engineering to enhance nogalamycin production in Streptomyces nogalater. In this work, we used an optimized soytone glucose production medium to produce nogalamycin. We also overexpressed copies of structural biosynthetic genes to bolster substrate precursor building blocks for nogalamycin production. First, overexpression of the TDP-glucose synthase and TDP-D-glucose-4,6-dehydratase enzymes (mtmDE) resulted in a 50% increase in nogalamycin production (160 mg/L) as compared to wildtype S. nogalater (100 mg/L). Secondly, overexpression of the minimal polyketide synthase genes (snoa123) resulted in a fourfold production increase in nogalamycin (400 mg/L). This production platform will serve as the fundament for production of nogalamycin analogues for future drug development efforts.

microbiology↗