Biology subjects

McPherson, H.

Publications and source records attributed to McPherson, H..

3 recordsLinked to original sources

bioRxiv2025

Whole-organism screening in a zebrafish model of CLN2 disease identifies pregnenolone as a modulator of lysosomal functions with anti-epileptic properties

Lysosomal storage disorders (LSDs), a group of inherited genetic diseases, are often associated with early-onset neurodegeneration and refractory epileptic seizures. In CLN2 disease, an LSD caused by recessively inherited dysfunction of lysosomal serine protease Tripeptidyl Peptidase 1 (TPP1), lysosomes are functionally impaired through a characteristic accumulation of subcellular materials. Here, we develop and apply a whole-organism screening workflow in tpp1-/- zebrafish to identify small molecules that suppress epileptic seizures - a hallmark of the human disease - in this model. Among 640 US Food and Drug Administration-approved drugs, pregnenolone, an endogenous precursor for steroid biosynthesis, efficiently suppresses seizures and cell death in tpp1-/- zebrafish. Using a semi-automated high-content workflow, we further show that pregnenolone normalizes lysosomal architecture in tpp1-/- zebrafish. Pregnenolone stimulates steroid hormone biosynthesis and related gene expression, which is dysregulated in tpp1-/- zebrafish. Taken together, tpp1-/- zebrafish are a suitable model to study CLN2 disease, in which we have identified pregnenolone as a candidate with therapeutic properties.

pharmacology and toxicology↗

bioRxiv2023

The genome of the Wollemi pine, a critically endangered living fossil unchanged since the Cretaceous, reveals extensive ancient transposon activity.

We present the genome of the living fossil, Wollemia nobilis, a southern hemisphere conifer morphologically unchanged since the Cretaceous. Presumed extinct until rediscovery in 1994, the Wollemi pine is critically endangered with less than 60 wild adults threatened by intensifying bushfires in the Blue Mountains of Australia. The 12 Gb genome is among the most contiguous large plant genomes assembled, with extremely low heterozygosity and unusual abundance of DNA transposons. Reduced representation and genome re-sequencing of individuals confirms a relictual population since the last major glacial/drying period in Australia, 120 ky BP. Small RNA and methylome sequencing reveal conservation of ancient silencing mechanisms despite the presence of thousands of active and abundant transposons, including some transferred horizontally to conifers from arthropods in the Jurassic. A retrotransposon burst 8-6 my BP coincided with population decline, possibly as an adaptation enhancing epigenetic diversity. Wollemia, like other conifers, is susceptible to Phytophthora, and a suite of defense genes, similar to those in loblolly pine, are targeted for silencing by sRNAs in leaves. The genome provides insight into the earliest seed plants, while enabling conservation efforts.

genomics↗

bioRxiv2021

Fibrinogen αC-subregions critically contribute blood clot fibre growth, mechanical stability and resistance to fibrinolysis

Fibrinogen is essential for blood coagulation. The C-terminus of the fibrinogen -chain (C-region) is composed of an C-domain and C-connector. Two recombinant fibrinogen variants (390 and 220) were produced to investigate the role of subregions in modulating clot stability and resistance to lysis. The 390 variant, truncated before the C-domain, produced clots with a denser structure and thinner fibres. In contrast, the 220 variant, truncated at the start of the C-connector, produced clots that were porous with short stunted fibres and visible fibre ends. These clots were mechanically weak and susceptible to lysis. Our data demonstrate differential effects for the C-subregions in fibrin polymerisation, clot mechanical strength, and fibrinolytic susceptibility. Furthermore, we demonstrate that the C-subregions are key for promoting longitudinal fibre growth. Together, these findings highlight critical functions of the C-subregions in relation to clot structure and stability, with future implications for development of novel therapeutics for thrombosis.

physiology↗