Salas-Allende, I. | bioRxiv Science

bioRxiv2022

The proto-oncogene DEK regulates neuronal excitability and tau accumulation in Alzheimer's disease vulnerable neurons

Neurons from layer II of the entorhinal cortex (ECII) are the first to accumulate tau protein aggregates and degenerate during prodromal Alzheimers disease. Here, we use a data-driven functional genomics approach to model ECII neurons in silico and identify the proto-oncogene DEK as a potential driver of tau pathology. By modulating DEK levels in EC neurons in vitro and in vivo, we first validate the accuracy and cell-type specificity of our network predictions. We then show that Dek silencing changes the inducibility of immediate early genes and alters neuron excitability, leading to dysregulation of neuronal plasticity genes. We further find that loss of function of DEK leads to tau accumulation in the soma of ECII neurons, reactivity of surrounding microglia, and eventually microglia-mediated neuron loss. This study validates a pathological gene discovery tool that opens new therapeutic avenues and sheds light on a novel pathway driving tau pathology in vulnerable neurons.

neuroscience↗

bioRxiv2019

Preoptic galanin neuron activation is specific to courtship reproductive tactic in fish with two male morphs

Species exhibiting alternative reproductive tactics (ARTs) provide ideal models for investigating neural mechanisms underlying robust and consistent differences in social behavioral phenotypes between individuals within a single sex. Using phospho-S6 protein (pS6), a neural activity marker, we investigate the activation of galanin-expressing neurons in the preoptic area-anterior hypothalamus (POA-AH) during ARTs in midshipman fish (Porichthys notatus) that have two adult male morphs: type I's that reproduce using an acoustic-dependent courtship tactic or a cuckolding tactic, and type II's that only cuckold. The proportion of pS6-labelled galanin neurons increases during mating by courting type I males, but not cuckolders of either male morph or females, and is not explained by vocalization, eggs in the nest, or cuckolders present during mating. These differences within the same behavioral context indicate a male phenotype-specific role for galanin neurons in mating interactions, providing the most direct evidence to date for the role of a specific neuronal population in the differential activation of one mating behavior over the other in species exhibiting ARTs. More broadly, together with their known role in mammalian mating, the results suggest a deep-rooted, phylogenetically shared function for POA-AH galanin neurons in reproductive behavior. As such, these findings also provide new insights into the evolutionary relationship between POA-AH populations involved in social behavior regulation in teleosts, the most species-rich vertebrate group, with those in the more highly differentiated POA-AH of mammals.

neuroscience↗