The Nuclear Import Receptor Kapβ2 Modifies Neurotoxicity Mediated by Poly(GR) in C9orf72-linked ALS/FTD

Overview

Journal Commun Biol

Specialty Biology

Date 2024 Mar 29

PMID 38548902

Authors

M E Cicardi

V Kankate

S Sriramoji

K Krishnamurthy

S S Markandaiah

B M Verdone

A Girdhar

A Nelson

L B Rivas

A Boehringer

A R Haeusler

P Pasinelli

L Guo

D Trotti

Affiliations

Soon will be listed here.

Abstract

Expanded intronic GC repeats in the C9ORF72 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These intronic repeats are translated through a non-AUG-dependent mechanism into five different dipeptide repeat proteins (DPRs), including poly-glycine-arginine (GR), which is aggregation-prone and neurotoxic. Here, we report that Kapβ2 and GR interact, co-aggregating, in cultured neurons in-vitro and CNS tissue in-vivo. Importantly, this interaction significantly decreased the risk of death of cultured GR-expressing neurons. Downregulation of Kapβ2 is detrimental to their survival, whereas increased Kapβ2 levels mitigated GR-mediated neurotoxicity. As expected, GR-expressing neurons displayed TDP-43 nuclear loss. Raising Kapβ2 levels did not restore TDP-43 into the nucleus, nor did alter the dynamic properties of GR aggregates. Overall, our findings support the design of therapeutic strategies aimed at up-regulating Kapβ2 expression levels as a potential new avenue for contrasting neurodegeneration in C9orf72-ALS/FTD.

Citing Articles

Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD.

Khalil B, Linsenmeier M, Smith C, Shorter J, Rossoll W Mol Neurodegener. 2024; 19(1):8.

PMID: 38254150 PMC: 10804745. DOI: 10.1186/s13024-023-00698-1.

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