Accumulation of TDP-43 causes karyopherin-α4 pathology that characterises amyotrophic lateral sclerosis

Topic: Brain proteins, microglia and lab models

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.

@article{atwal2025-40772263,
  author  = {Atwal, Manpreet Singh and Nimac, Jerneja and Čerček, Urša and Goesch, Sarah Ricarda and Goesch, Hannah Rebecca and Tziortzouda, Paraskevi and Ercolani, Tiziana and Zatorska, Anna and others},
  title   = {{Accumulation of TDP-43 causes karyopherin-α4 pathology that characterises amyotrophic lateral sclerosis}},
  journal = {Frontiers in Neuroscience},
  year    = {2025},
  doi     = {10.3389/fnins.2025.1558227},
  pmid    = {40772263},
  url     = {https://doi.org/10.3389/fnins.2025.1558227}
}

Key findings

• Structural analyses revealed the selective interaction between KPNA subtypes, especially KPNA4, with the nuclear localisation signal (NLS) of TDP-43.
• 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.

Why it matters

This study reports karyopherin-α4 pathology in the spinal cord of TDP-43-positive sporadic ALS and C9ALS patients, and shows in human cells and fruit flies that cytoplasmic accumulation of TDP-43 causes this karyopherin pathology. It identifies KPNA4 as a potential therapeutic target but does not test any treatment, cure or prevention in patients.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.3389/fnins.2025.1558227
• PubMed: 40772263
• Original source →
• Free full text: Frontiers in Neuroscience →

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Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 19.

• TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis Science · 2008-02-28 · usefulness score 64/100 · Disease mechanisms
• A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD Neuron · 2011-09-21 · usefulness score 63/100 · Lewy body dementia
• Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science (New York, N.Y.) · 2006-10-01 · usefulness score 62/100 · Lewy body dementia
• Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS Neuron · 2011-09-21 · usefulness score 62/100 · Lewy body dementia
• TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD Nature neuroscience · 2018-01-08 · usefulness score 61/100 · Lewy body dementia
• The overlap of amyotrophic lateral sclerosis and frontotemporal dementia Neurology · 2002-10-01 · usefulness score 59/100 · Getting a diagnosis
• TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions The American journal of pathology · 2007-07-01 · usefulness score 59/100 · Lewy body dementia
• The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS Science (New York, N.Y.) · 2013-02-07 · usefulness score 59/100 · Lewy body dementia
• Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS Nature neuroscience · 2015-09-01 · usefulness score 59/100 · Lewy body dementia
• Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis Neuron · 2013-08-01 · usefulness score 58/100 · Lewy body dementia
• GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport Nature · 2015-08-26 · usefulness score 58/100 · Lewy body dementia
• The C9orf72 repeat expansion disrupts nucleocytoplasmic transport Nature · 2015-08-26 · usefulness score 57/100 · Lewy body dementia

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• Alzheimer's Disease Co-Pathology and Cognitive Impairment in Amyotrophic Lateral Sclerosis Annals of neurology · 2026-05-11 · usefulness score 57/100
• Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations Annals of neurology · 2007-05-01 · usefulness score 63/100
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• TDP-43 in amyotrophic lateral sclerosis - is it a prion disease? European journal of neurology · 2015-05 · usefulness score 38/100
• Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72 Brain : a journal of neurology · 2012-03-01 · usefulness score 62/100

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• Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis 2019 · Lewy body dementia
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