Quo vadis PGRMC? Grand-Scale Biology in Human Health and Disease

Abstract

The title usage of Latin Quo vadis 'where are you going' extends the question Unde venisti from where 'did you come?' posed in the accompanying paper and extends consideration of how ancient eukaryotic and eumetazoan functions of progesterone receptor membrane component (PGRMC) proteins (PGRMC1 and PGRMC2 in mammals) could influence modern human health and disease. This paper attempts to extrapolate to modern biology in terms of extensions of hypothetical ancestral functional states from early eukaryotes and the last eumetazoan common ancestor (LEUMCA), to relativize human metabolic physiology and disease. As novel cell types and functional specializations appeared in bilaterian animals, PGRMC functions are hypothesized to have continued to be part of the toolkit used to develop new cell types and manage increasingly complex tasks such as nerve-gut-microbiome neuronal and hormonal communication. A critical role of PGRMC (as one component of a new eumetazoan genetic machinery) is proposed in LEUMCA endocrinology, neurogenesis, and nerve-gut communication with possible involvement in circadian nicotinamide adenine dinucleotide synthesis. This model would explain the contribution of PGRMC to metabolic and differentiation/behavioral changes observed in age-related diseases like diabetes, cancer and perhaps aging itself. Consistent with proposed key regulation of neurogenesis in the LEUMCA, it is argued that Alzheimer's disease is the modern pathology that most closely reflects the suite of functions related to PGRMC biology, with the 'usual suspect' pathologies possibly being downstream of PGRMC1. Hopefully, these thoughts help to signpost directions for future research.

Unde venisti PGRMC? Grand-Scale Biology from Early Eukaryotes and Eumetazoan Animal Origins

“…There, it associates with promoters with binding sites for the TCF/Lef transcription factor, where Tcf/Lef-dependent transcriptional activity is enhanced in the absence of P4, or suppressed in the presence of P4 [142][143][144]. TCF/Lef is the target of the Wnt/β-catenin pathway, which will be discussed further in the accompanying manuscript [2]. TCF/Lef target promoters include many immediate early genes, including c-myc, whose induction leads to increased metabolic activity in the G1 cell cycle phase, and promotes regulatable transition of the G1 checkpoint and entry to the cell cycle, at least in granulosa cells [144].…”

“…Perhaps most poignantly for synaptic origins, PGRMC1 membrane trafficking is required for the mechanism of action of new anti-AD drugs that displace Aβo from synapses, to improve synaptic strength and cognitive ability in rodent models of AD [63,64]. One of these compounds is currently in clinical trial for the treatment of AD [65,222,[323][324][325][326] (see conflict of interest statement): topic covered in detail in the accompanying paper [2].…”

“…As such, they may have been foundational to the evolution of PSCs. These themes are revisited in the accompanying paper in consideration of Alzheimer's disease and aging [2].…”

“…Fundamentally, this work pursues the metabolism aspect of PRMC1, including consideration of age-related diseases such as cancer and diabetes, with special focus on the related cell and metabolic changes associated with the neuropathology of Alzheimer's disease (AD) and possibly aging itself. These will be addressed in the accompanying paper [2] after this present paper builds a conceptual platform.…”

“…Rather, I will focus on the proposed role of an ancestral MAPR protein in eukaryogenesis, and much later of the proposed involvement of PGRMC in the origins of the gastrulation organizer, and the system of eumetazoan body pattern formation that it may have foundationally enabled. The accompanying paper [2] will consider how this combined biological panoply is relevant for our mechanistic understanding of several modern clinical pathologies.…”