Work

Mislocalization of FTD3-associated mutant CHMP2B to the nucleus of human neurons due to loss of a nuclear export signal

Year: 2026

Type: article

Abstract: Frontotemporal dementia linked to chromosome 3 (FTD3) is caused by a splice site point mutation in CHMP2B , resulting in the production of mutant proteins CHMP2B In5 and CHMP2B Δ10 . Here, we found that wildtype CHMP2B (CHMP2B WT ) is mostly present in the cytoplasm, but CHMP2B In5 is mislocalized to the nucleus of human induced pluripotent stem cell (iPSC)-derived cortical neurons. To understand the underlying mechanism, we identified a previously unreported nuclear export signal (NES) in the C-terminus of CHMP2B. Functional assays, including CRM1 inhibition and site-directed mutagenesis of key hydrophobic residues, demonstrated that this NES motif is both necessary and sufficient for nuclear export of CHMP2B WT and ALS-associated CHMP2B Q206H , and its loss in CHMP2B In5 is responsible for the observed nuclear mislocalization. CHMP2B Δ10 remains in the cytoplasm due to the presence of an artificial NES in the C-terminus. These results reveal the presence of an NES in CHMP2B and highlight the need to dissect the gain-of-toxic nuclear functions of CHMP2B In5 in FTD3 pathogenesis.

Source: Acta Neuropathologica Communications

DOI: 10.1186/s40478-026-02222-0

Authors: Yong-Woo Jun, Evan P. Hass, Soojin Lee, Thomas G. Fazzio, Fen-Biao Gao

Institution: University of Massachusetts Chan Medical School

Language: English

Topic: Amyotrophic Lateral Sclerosis Research

Subfield: Neurology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,790