Biology subjects

Greer, P. L.

Publications and source records attributed to Greer, P. L..

4 recordsLinked to original sources

bioRxiv2024

RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition, with 20% of familial and 2-3% of sporadic cases linked to mutations in the cytosolic superoxide dismutase (SOD1) gene. Mutant SOD1 protein is toxic to motor neurons, making SOD1 gene lowering a promising approach, supported by preclinical data and the 2023 FDA approval of the GapmeR ASO targeting SOD1, tofersen. Despite the approval of an ASO and the optimism it brings to the field, the pharmacodynamics and pharmacokinetics of therapeutic SOD1 modulation can be improved. Here, we developed a chemically stabilized divalent siRNA scaffold (di-siRNA) that effectively suppresses SOD1 expression in vitro and in vivo. With optimized chemical modification, it achieves remarkable CNS tissue permeation and SOD1 silencing in vivo. Administered intraventricularly, di-siRNASOD1 extended survival in SOD1-G93A ALS mice, surpassing survival previously seen in these mice by ASO modalities, slowed disease progression, and prevented ALS neuropathology. These properties offer an improved therapeutic strategy for SOD1-mediated ALS and may extend to other dominantly inherited neurological disorders. One sentence summarySilencing SOD1 with chemically optimized divalent siRNA profoundly extends the lifespan of G93A mice and prevents neurodegenerative biochemical and behavioral phenotypes.

neuroscience↗

bioRxiv2023

CD20 is a mammalian odorant receptor expressed in a subset of olfactory sensory neurons that mediates innate avoidance of predators

The mammalian olfactory system detects and discriminates between millions of odorants to elicit appropriate behavioral responses. While much has been learned about how olfactory sensory neurons detect odorants and signal their presence, how specific innate, unlearned behaviors are initiated in response to ethologically relevant odors remains poorly understood. Here, we show that the 4-transmembrane protein CD20, also known as MS4A1, is expressed in a previously uncharacterized subpopulation of olfactory sensory neurons in the main olfactory epithelium of the murine nasal cavity and functions as a mammalian odorant receptor that recognizes compounds produced by mouse predators. While wild-type mice avoid these predator odorants, mice genetically deleted of CD20 do not appropriately respond. Together, this work reveals a novel CD20-mediated odor-sensing mechanism in the mammalian olfactory system that triggers innate behaviors critical for organismal survival.

animal behavior and cognition↗

bioRxiv2023

Selenium reduction of ubiquinone via SQOR suppresses ferroptosis

The canonical biological function of selenium is in the production of selenocysteine residues of selenoproteins, and this forms the basis for its role as an essential antioxidant and cytoprotective micronutrient. Here, we demonstrate that selenium, via its metabolic intermediate hydrogen selenide, efficiently donates its electrons to ubiquinone to form ubiquinol in the mitochondria through catalysis by sulfide quinone oxidoreductase (SQOR). Hydrogen selenide is superior to hydrogen sulfide as an electron donor owing to its larger valence shell. We show that this mechanism, independently of selenoprotein production, protects against ferroptosis via ubiquinol production in a manner that depends on xCT mediated selenide formation and SQOR activity. Our findings identify a regulatory mechanism against ferroptosis that implicates SQOR and expands our understanding of selenium in biology.

biochemistry↗

bioRxiv2020

Role of Epigenetics in Unicellular to Multicellular Transition in Dictyostelium

The evolution of multicellularity is a critical event that remains incompletely understood. We use the social amoeba, Dictyostelium discoideum, one of the rare organisms that exists in both unicellular and multicellular stages, to examine the role of epigenetics in regulating multicellularity. While transitioning to multicellular states, patterns of H3K4 methylation and H3K27 acetylation significantly change. By combining transcriptomics, epigenomics, chromatin accessibility, and syntenic analyses with other unicellular and multicellular organisms, we identify 52 conserved genes, which are specifically accessible and expressed during multicellular states. We validated that four of these genes, including the H3K27 deacetylase hdaD, are necessary and that an SMC-like gene, smcl1, is sufficient for multicellularity. These results highlight the importance of epigenetics in reorganizing chromatin architecture to facilitate the evolution of multicellularity. One Sentence SummaryEpigenetic regulation of multicellularity

genetics↗