Biology subjects

Clark, A. F.

Publications and source records attributed to Clark, A. F..

3 recordsLinked to original sources

bioRxiv2025

Mechanistic insights into glucocorticoid-induced ocular hypertension using differences in mouse strain responsiveness

Glucocorticoids (GCs) are widely prescribed anti-inflammatory agents. Unfortunately, many people experience negative side-effects associated with long term GC therapy, developing GC-induced ocular hypertension (GC-OHT), which can lead to secondary glaucoma. Approximately, 40% of the treated individuals are susceptible to GC-OHT. Seventy years since this discovery, the molecular mechanisms underlying GC-OHT remain unclear. We previously developed a mouse model of GC-OHT delivering the potent GC dexamethasone (DEX) and observed strain-specific disparities in the development of GC-OHT. We now compare phenotypic and transcriptomic differences between five genetically distinct inbred mouse strains to identify biomarkers of GC susceptibility, and to better understand the molecular mechanisms of GC-OHT. Like humans, mouse strains differ in their ability to develop GC-OHT. Phenotypic characterization revealed that C57BL/6J and C3H/HeJ mice are GC responders and more susceptible to develop GC-OHT. DEX treatment in these strains led to elevated IOP compared to the GC non-responder strains DBA/2J.Gpnmb+, 129P3/J, and BALB/cJ. Transcriptomic analysis of responder and non-responder mouse strains revealed novel trabecular meshwork (TM) biomarkers of GC-OHT susceptibility involving enrichment of molecular pathways unique to this response. Our study identifies putative mechanisms underlying GC-OHT and provides insight into the pathogenesis of the clinically similar but more prevalent primary open-angle glaucoma.

pathology↗

bioRxiv2025

Phenethylaminylation: Preliminary In Vitro Evidence for the Covalent Transamidation of Psychedelic Phenethylamines to Glial Proteins using 3,5-Dimethoxy-4-(2-Propynyloxy)-Phenethylamine as a Model Compound

Psychedelics are well known for their ability to produce profoundly altered states of consciousness. But, more importantly, the effects of psychedelics can influence neurobehavioral changes that last well after these acute subjective effects end. This phenomenon is currently being leveraged in the development of psychedelic-assisted psychotherapies for the treatment of multiple neuropsychiatric disorders. The cellular and molecular mechanisms by which single doses of psychedelics are able to mediate long-term cognitive changes are an active area of research. We hypothesize that psychedelics contribute to long term changes in cellular state by covalently modifying proteins. This post-translational modification by psychedelics is possible through the transglutaminase-mediated transamidation of their amine termini to glutamine carboxamide residues. Here, we synthesize and utilize a propargylated analogue of mescaline - the classic serotonergic psychedelic phenethylamine found in cacti species - to identify putative protein targets of psychedelic modifications through the use of click-chemistry in a primary human astrocyte cell culture model. Our preliminary findings indicate that a diverse array of glial proteins may be substrates for transglutaminase 2-mediated monoaminylation by our model phenethylamine ("phenethylaminylation"). Based on these points, we speculatively highlight new directions for the study of this putative noncanonical psychedelic activity.

molecular biology↗

bioRxiv2025

Genetic and pharmacological correction of impaired mitophagy in retinal ganglion cells rescues glaucomatous neurodegeneration

Progressive loss of retinal ganglion cells (RGCs) and degeneration of optic nerve axons are the pathological hallmarks of glaucoma. Ocular hypertension (OHT) and mitochondrial dysfunction are linked to neurodegeneration and vision loss in glaucoma. However, the exact mechanism of mitochondrial dysfunction leading to glaucomatous neurodegeneration is poorly understood. Using multiple mouse models of OHT and human eyes from normal and glaucoma donors, we show that OHT induces impaired mitophagy in RGCs, resulting in the accumulation of dysfunctional mitochondria and contributing to glaucomatous neurodegeneration. Using mitophagy reporter mice, we show that impaired mitophagy precedes glaucomatous neurodegeneration. Notably, the pharmacological rescue of impaired mitophagy via Torin-2 or genetic upregulation of RGC-specific Parkin expression restores the structural and functional integrity of RGCs and their axons in mouse models of glaucoma and ex-vivo human retinal-explant cultures. Our study indicates that impaired mitophagy contributes to mitochondrial dysfunction and oxidative stress, leading to glaucomatous neurodegeneration. Enhancing mitophagy in RGCs represents a promising therapeutic strategy to prevent glaucomatous neurodegeneration. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/638142v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1620793org.highwire.dtl.DTLVardef@df5a25org.highwire.dtl.DTLVardef@1974c34org.highwire.dtl.DTLVardef@bf605_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

neuroscience↗