The nuclear import receptor Kapβ2 modifies neurotoxicity mediated by poly(GR) in C9orf72-linked ALS/FTD

Expanded intronic G 4 C 2 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), w...

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Published in:	Communications biology Vol. 7; no. 1; p. 376
Main Authors:	Cicardi, M. E., Kankate, V., Sriramoji, S., Krishnamurthy, K., Markandaiah, S. S., Verdone, B. M., Girdhar, A., Nelson, A., Rivas, L. B., Boehringer, A., Haeusler, A. R., Pasinelli, P., Guo, L., Trotti, D.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 28-03-2024 Nature Publishing Group Nature Portfolio
Subjects:	14/19 14/33 631/378/1689/1285 631/378/1934 64/110 82/1 Active Transport, Cell Nucleus Amyotrophic lateral sclerosis Amyotrophic Lateral Sclerosis - genetics Amyotrophic Lateral Sclerosis - metabolism Biomedical and Life Sciences C9orf72 Protein - genetics Dementia disorders DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Down-regulation Frontotemporal dementia Frontotemporal Dementia - genetics Humans Life Sciences Neurodegeneration Neurotoxicity Nuclear transport Receptors, Cytoplasmic and Nuclear - metabolism
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Summary:	Expanded intronic G 4 C 2 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. Expanded intronic G 4 C 2 repeats in C9orf72 cause ALS/FTD. GR dipeptide repeats produced in C9orf72 ALS/FTD co-aggregate with Kap2 in neurons, affecting survival. Upregulating Kapβ2 may mitigate neurotoxicity, a potential therapy for C9orf72-ALS/FTD.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2399-3642 2399-3642
DOI:	10.1038/s42003-024-06071-2