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Peer-reviewedCC BY-NC-ND 4.0Acta Neuropathologica Communications

TDP-43-related cryptic splicing reflects pathological heterogeneity in amyotrophic lateral sclerosis

  • Ichiko Ikegami1
  • Shoko Hongo1,2,3
  • Akihide Koyama4
  • Yoshika Hayakawa-Yano5
  • Masato Yano5
  • Akihiro Sugai1
  • Tomohiko Ishihara1
  • Mari Tada2,3
  • Akiyoshi Kakita2,3
  • Osamu Onodera1
  • Yuka Mitsuhashi Koike1
5 affiliations
  1. 1Department of Neurology, Brain Research Institute, Niigata University, Niigata, 951-8585 Japan
  2. 2Department of Pathology, Brain Research Institute, Niigata University, Niigata, 951-8585 Japan
  3. 3Center for Human Brain Resource Initiative (ChBRI), Niigata University, Niigata, 951-8122 Japan
  4. 4Department of Legal Medicine, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, 951-8585 Japan
  5. 5Core Research Facilities for Basic Science, Research Center for Medical Science, The Jikei University School of Medicine, Tokyo, 105-8461 Japan
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Abstract

Amyotrophic lateral sclerosis (ALS) involves TAR DNA-binding protein 43 (TDP-43) dysfunction, leading to cryptic splicing, including UNC13A cryptic exon inclusion and truncated STMN2 production. Pathologically, ALS is classified into three phosphorylated TDP-43 subtypes (Types 1, 2a, and 2b) based on the distribution of neuronal and glial cytoplasmic inclusions and the density of dystrophic neurites. However, the relationship between these pathological subtypes and TDP-43-associated cryptic splicing remains unclear. This retrospective postmortem study aimed to analyze motor cortex tissue from sporadic ALS cases (Type 1, n = 12; Type 2a, n = 12; Type 2b, n = 11) with previously described subtype-specific morphological features. UNC13A cryptic RNA and truncated STMN2 RNA levels were quantified using quantitative real-time PCR (qRT-PCR). Compared with Types 1 and 2a, Type 2b, characterized by abundant thread-, dot-, and grain-like dystrophic neurites, exhibited significantly higher levels of UNC13A cryptic RNA and truncated STMN2 RNA. Droplet digital PCR revealed a similar subtype-dependent trend and showed strong correlations with qRT-PCR measurements, providing partial support for the primary findings. UNC13A cryptic RNA and truncated STMN2 RNA levels were positively correlated (Spearman’s ρ = 0.58), indicating coordinated dysregulation of multiple TDP-43-dependent splicing targets. Our results demonstrate that the burden of TDP-43-associated cryptic splicing differs across ALS pathological subtypes. Additional analyses indicated that these subtype-dependent differences were not readily accounted for by disease duration, RNA quality, normalization strategy, or semiquantitative neuronal loss scores. These findings suggest that molecular heterogeneity parallels pathological heterogeneity in ALS and provide additional insight into the biological diversity of TDP-43 proteinopathy.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s40478-026-02400-0.

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Cite

BibTeXRIS
BibTeX
@article{ikegami2026tdp43related,
  title = {{TDP-43-related cryptic splicing reflects pathological heterogeneity in amyotrophic lateral sclerosis}},
  author = {Ichiko Ikegami and Shoko Hongo and Akihide Koyama and Yoshika Hayakawa-Yano and Masato Yano and Akihiro Sugai and Tomohiko Ishihara and Mari Tada and Akiyoshi Kakita and Osamu Onodera and Yuka Mitsuhashi Koike},
  journal = {Acta Neuropathologica Communications},
  year = {2026},
  month = aug,
  doi = {10.1186/s40478-026-02400-0},
  url = {https://doi.org/10.1186/s40478-026-02400-0},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - TDP-43-related cryptic splicing reflects pathological heterogeneity in amyotrophic lateral sclerosis
AU  - Ichiko Ikegami
AU  - Shoko Hongo
AU  - Akihide Koyama
AU  - Yoshika Hayakawa-Yano
AU  - Masato Yano
AU  - Akihiro Sugai
AU  - Tomohiko Ishihara
AU  - Mari Tada
AU  - Akiyoshi Kakita
AU  - Osamu Onodera
AU  - Yuka Mitsuhashi Koike
PY  - 2026
DA  - 2026/08/08
JO  - Acta Neuropathologica Communications
DO  - 10.1186/s40478-026-02400-0
UR  - https://doi.org/10.1186/s40478-026-02400-0
AB  - Amyotrophic lateral sclerosis (ALS) involves TAR DNA-binding protein 43 (TDP-43) dysfunction, leading to cryptic splicing, including UNC13A cryptic exon inclusion and truncated STMN2 production. Pathologically, ALS is classified into three phosphorylated TDP-43 subtypes (Types 1, 2a, and 2b) based on the distribution of neuronal and glial cytoplasmic inclusions and the density of dystrophic neurites. However, the relationship between these pathological subtypes and TDP-43-associated cryptic splicing remains unclear. This retrospective postmortem study aimed to analyze motor cortex tissue from sporadic ALS cases (Type 1, n = 12; Type 2a, n = 12; Type 2b, n = 11) with previously described subtype-specific morphological features. UNC13A cryptic RNA and truncated STMN2 RNA levels were quantified using quantitative real-time PCR (qRT-PCR). Compared with Types 1 and 2a, Type 2b, characterized by abundant thread-, dot-, and grain-like dystrophic neurites, exhibited significantly higher levels of UNC13A cryptic RNA and truncated STMN2 RNA. Droplet digital PCR revealed a similar subtype-dependent trend and showed strong correlations with qRT-PCR measurements, providing partial support for the primary findings. UNC13A cryptic RNA and truncated STMN2 RNA levels were positively correlated (Spearman’s ρ = 0.58), indicating coordinated dysregulation of multiple TDP-43-dependent splicing targets. Our results demonstrate that the burden of TDP-43-associated cryptic splicing differs across ALS pathological subtypes. Additional analyses indicated that these subtype-dependent differences were not readily accounted for by disease duration, RNA quality, normalization strategy, or semiquantitative neuronal loss scores. These findings suggest that molecular heterogeneity parallels pathological heterogeneity in ALS and provide additional insight into the biological diversity of TDP-43 proteinopathy.  Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s40478-026-02400-0.
SN  - 2051-5960
ER  -