Toxicity of MAPT 4R RNA Contributes to Motor Neuron Degeneration in ALS

Authors

Crerar, H., Stasi, M., Pal, K., Nuccio, S., Petric-Howe, M., Manferrari, G., Wang, Y., Clarke, B., Ruepp, M.-D. G., Di Antonio, M., Patani, R.

Abstract

MAPT (Tau) dysregulation is implicated in several neurodegenerative diseases, but its contribution to amyotrophic lateral sclerosis (ALS) is poorly understood. Here we show that mRNA isoforms encoding 4-repeat (4R) Tau are upregulated and cytoplasmically enriched in iPSC-derived motor neurons (MNs) from VCP-mutant and sporadic ALS, without a corresponding change in Tau protein. Using splice-switching antisense oligonucleotides and isoform-specific siRNAs, we find that enhanced 4R expression reduces MN viability, whereas its selective knockdown improves survival, with kinetics more consistent with an RNA-intrinsic effect than altered protein synthesis. Exon 10-containing MAPT RNA shows increased predicted secondary structure, self-association and altered Tau biocondensation in vitro. In post-mortem ALS cervical spinal cord, increased relative exon 10 usage is associated with a higher-risk clinical phenotype and shorter disease duration These findings identify an isoform-specific contribution of MAPT to MN vulnerability in ALS and nominate 4R MAPT RNA as a therapeutic target.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 30 Sep 2026.

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