Biology subjects

Plautz, Z.

Publications and source records attributed to Plautz, Z..

2 recordsLinked to original sources

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↗

bioRxiv2018

Selective neuronal vulnerability in Alzheimer’s disease: a network-based analysis

A major obstacle to treating Alzheimers disease (AD) is our lack of understanding of the molecular mechanisms underlying selective neuronal vulnerability, which is a key characteristic of the disease. Here we present a framework to integrate high-quality neuron-type specific molecular profiles across the lifetime of the healthy mouse, which we generated using bacTRAP, with postmortem human functional genomics and quantitative genetics data. We demonstrate human-mouse conservation of cellular taxonomy at the molecular level for AD vulnerable and resistant neurons, identify specific genes and pathways associated with AD pathology, and pinpoint a specific functional gene module underlying selective vulnerability, enriched in processes associated with axonal remodeling, and affected by both amyloid accumulation and aging. Overall, our study provides a molecular framework for understanding the complex interplay between A{beta}, aging, and neurodegeneration within the most vulnerable neurons in AD.

neuroscience↗