# Expression of progerin enhances disease-related endpoints in a tau seeding reporter cell system

## TL;DR

This study shows that expressing progerin, a protein linked to premature aging, makes cells more sensitive to harmful tau protein changes seen in brain diseases like Alzheimer's.

## Contribution

The novel finding is that progerin expression enhances tau seeding effects without generating new tau strains.

## Key findings

- Progerin-expressing cells showed increased ER stress markers like DNAJC10 and DNAJA2 when exposed to tau conformers.
- The effect of progerin was additive with tau seeding but did not depend on the specific tau strain used.
- Combining progerin and tau stressors caused notable changes in cellular homeostasis.

## Abstract

Sporadic Alzheimer’s disease and some forms of frontotemporal lobar degeneration (FTLD-tau) are neurological disorders of later life where cognitive deficits follow from the progressive accumulation of microtubule-associated tau protein. Disease-related tau accumulation is marked by altered subcellular distribution and rearrangement of this natively unstructured protein into alternative conformational forms, including highly organized fibrillar assemblies. With a partial analogy to effects seen in prion diseases, pathological tau conformers have a templating activity called seeding that may be measured in cellular and cell-free systems. Moreover, cellular systems and disease models can recapitulate “strain effects” wherein the same tau amino acid sequence can adopt markedly different conformations. Here we analyzed FTLD-tau conformers in cellular reporter systems expressing a pro-aging mutant form of the lamin A protein termed “progerin.” Measured versus the baseline performance of a reporter system based on HEK293 cells, the addition of tau burden or progerin expression produced only mild changes in proteomic analyses or morphology, whereas application of both stressors produced a notable shift in ER stress and homeostasis, including increased levels of DNAJC10 and DNAJA2. The phenotypic effects scored here appear unrelated to the generation of new tau strains or to the type of strain input, insofar as progerin-expressing cells were more responsive to tau seeding by diverse brain samples containing different populations of tau conformers. Thus, premature aging and disease-associated tau conformers can exhibit an additive relationship in a model system.

The online version contains supplementary material available at 10.1007/s11357-025-01737-z.