Accumulation of TDP-43 causes karyopherin-▫$\alpha$▫4 pathology that characterises amyotrophic lateral sclerosis

Atwal, Manpreet Singh (author), Nimac, Jerneja (author), Čerček, Urša (author), Goesch, Sarah Ricarda (author), Goesch, Hannah Rebecca (author), Tziortzouda, Paraskevi (author), Ercolani, Tiziana (author), Zatorska, Anna (author), Pasha, Terouz (author), Carre, Ivo (author), Mitchell, Jacqueline C. (author), Troakes, Claire (author), Tummers, Bart (author), Župunski, Vera (author), Rogelj, Boris (author), Hortobágyi, Tibor (author), Hirth, Frank (author)

Cytoplasmic mislocalisation and nuclear depletion of TDP-43 are pathological hallmarks of amyotrophic lateral sclerosis (ALS), including mutations in the C9ORF72 gene that characterise the most common genetic form of ALS (C9ALS). Studies in human cells and animal models have associated cytoplasmic mislocalisation of TDP-43 with abnormalities in nuclear transport receptors, referred to as karyopherins, that mediate the nucleocytoplasmic shuttling of TDP-43. Yet the relationship between karyopherin abnormalities and TDP-43 pathology are unclear. Here we report karyopherin-α4 (KPNA4) pathology in the spinal cord of TDP-43-positive sporadic ALS and C9ALS patients. Structural analyses revealed the selective interaction between KPNA subtypes, especially KPNA4, with the nuclear localisation signal (NLS) of TDP-43. Targeted cytoplasmic mislocalisation and nuclear depletion of TDP-43 caused KPNA4 pathology in human cells. Similar phenotypes were observed in Drosophila whereby cytoplasmic accumulation of the TDP-43 homolog, TBPH, caused the nuclear decrease and cytosolic mislocalisation of the KPNA4 homolog, Importin-α3 (Impα3). In contrast, induced accumulation of Impα3 was not sufficient to cause TBPH mislocalisation. Instead, targeted gain of Impα3 in the presence of accumulating cytosolic TBPH, restored Impα3 localisation and partially rescued nuclear TBPH. These results demonstrate that cytoplasmic accumulation of TDP-43 causes karyopherin pathology that characterises ALS spinal cord. Together with earlier reports, our findings establish KPNA4 abnormalities as a molecular signature of TDP-43 proteinopathies and identify it as a potential therapeutic target to sustain nuclear TDP-43 essential for cellular homeostasis affected in ALS and frontotemporal dementia.

• Language: English
• Keywords: C9ORF72, KPNA4, TDP-43, amyotrophic lateral sclerosis, karyopherin, nuclear import
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FKKT - Faculty of Chemistry and Chemical Technology; MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2025
• Number of pages: Str. 1-14
• Numbering: Vol. 19, art. 1558227
• PID: 20.500.12556/RUL-173661
• UDC: 577.112:616.8
• ISSN on article: 1662-453X
• DOI: 10.3389/fnins.2025.1558227
• COBISS.SI-ID: 246215171
• Publication date in RUL: 19.09.2025

Record is a part of a journal

• Title: Frontiers in neuroscience
• Shortened title: Front. neurosci.
• Publisher: Frontiers Research Foundation
• ISSN: 1662-453X
• COBISS.SI-ID: 522058521

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: C9ORF72, KPNA4, TDP-43, amiotrofična lateralna skleroza, karioferin, jedrni uvoz