# Exploring the Biological Connection Between Tau and PrPC in Neuronal Cells: GSK3β as a Possible Key Player

## TL;DR

This review explores how PrPC and tau proteins interact in neurons, with GSK3β possibly playing a key role in both normal brain function and neurodegenerative diseases.

## Contribution

The paper highlights a novel molecular connection between PrPC and tau, particularly through GSK3β regulation, in both health and disease.

## Key findings

- PrPC and tau share overlapping roles in neuronal differentiation and axonal maturation.
- PrPC influences tau splicing by inhibiting GSK3β, while tau can regulate PRNP transcription.
- Molecular convergence between PrPC and tau is discussed in neurodegeneration and natural physiology.

## Abstract

Cellular prion protein (PrPC) and tau are highly expressed in the brain and overlap at the cellular level in neurons. Both proteins contribute directly to neurodegeneration processes in a misfolding state, although in their natural conformation, they play important roles in neurogenesis that could have a common link according to the recent literature. In this sense, it is well known that the proteinase-K resistant PrPC isoform (PrPSc), the prion, is the causal agent of prionopathies. And misfolded tau, which is responsible for tauopathies, is considered “prion-like” because it displays similar behavior to prions in terms of self-aggregation and spreading properties. At the physiological level, PrPC potentiates neuronal differentiation while tau intervenes in axonal maturation and elongation. Likewise, recent studies from our laboratory reported that PrPC directly affects the alternative splicing of tau through inhibition of GSK3β while tau, in turn, can regulate PRNP transcription. In this review, we first describe the biology and physiological roles of PrPC and tau in the central nervous system (CNS). Second, in the effort to improve our understanding of a possible cooperation between them in various cellular circumstances, we also discuss the molecular convergence points between PrPC and tau in neurodegeneration and in natural neuronal physiology.

The online version contains supplementary material available at 10.1007/s12035-025-05163-2.