Nuclear Expression of TDP-43 Is Linked with Morphology and Ubiquitylation of Cytoplasmic Aggregates in Amyotrophic Lateral Sclerosis
Abstract
:1. Introduction
2. Results
2.1. Cases
2.1.1. TDP-43 Pathology in the Lower Motor Neuron System
2.1.2. Morphological Features of Cytoplasmic TDP-43 Inclusions Differed between TDP-43 n/c-ir and TDP-43 c-ir Neurons
2.1.3. Cytoplasmic TDP-43 Inclusions of n/c-ir Neurons Were Phosphorylated but Poorly Ubiquitylated
2.1.4. Nuclear TDP-43 Signal Intensity Was Lower in n/c-ir Neurons Than in Normal Neurons
2.2. TDP-43 n/c-ir Neurons in the Upper Motor Neuron System
2.3. TDP-43 n/c-ir Glia in the Motor Neuron System
2.4. TDP-43 n/c-ir Neurons Became Less Dominant with a Prolonged Disease Duration
3. Discussion
4. Materials and Methods
4.1. Cases
4.2. Clinical Analyses
4.3. Tissue Preparation
4.4. Immunohistochemistry
4.5. Immunofluorescence
4.6. Quantitative Analyses
4.7. Identification of TDP-43 c-ir and n/c-ir
4.8. Classification of Neuronal TDP-43 Aggregates
4.9. Colocalization Assay
4.10. Measurement of Nuclear Signal Intensity
4.11. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ALS | amyotrophic lateral sclerosis |
FTD | frontotemporal dementia |
FTLD | frontotemporal lobar degeneration |
LMN | lower motor neuron |
MND | motor neuron disease |
NNI | neuronal nuclear inclusions |
PMC | primary motor cortex |
p-TDP-43 | phosphorylated TDP-43 |
TDP-43 | transactive response DNA-binding protein of 43 kDa |
TDP-43 c-ir | TDP-43 cytoplasmic immunoreactivity |
TDP-43 n/c-ir | TDP-43 nuclear and cytoplasmic immunoreactivity |
UMN | upper motor neuron |
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ALS | Control | p | |
---|---|---|---|
n (female/male) | 22 (8f/14m) | 15 (3f/12m) | 0.466 * |
age at death (mean, SD) | 62.7 ± 10.1 | 69.7 ± 10.2 | 0.529 ** |
duration of disease (month, median, range) | 19 (6-132) | - | |
postmortem delay (hour, median, range) | 3 (1.5 − 24) | 9 (3.5 − 20) | 0.200 ** |
brain weight | 1298 ± 120 | 1260 ± 204 | 0.267 ** |
brain aging pathology | |||
Braak’s tau stage (mean, SD, range) | 1.5 ± 0.7 (I–III) | 1.7 ± 0.9 (0–III) | 0.447 ** |
Lewy body disease (mean, SD, range) | 0 | 0 | 1 |
Thal’s amyloid phase (mean, SD, range) | 0.7 ± 0.7 (0–2) | 0.7 ± 0.8 (0–2) | 0.984 ** |
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Yabata, H.; Riku, Y.; Miyahara, H.; Akagi, A.; Sone, J.; Urushitani, M.; Yoshida, M.; Iwasaki, Y. Nuclear Expression of TDP-43 Is Linked with Morphology and Ubiquitylation of Cytoplasmic Aggregates in Amyotrophic Lateral Sclerosis. Int. J. Mol. Sci. 2023, 24, 12176. https://doi.org/10.3390/ijms241512176
Yabata H, Riku Y, Miyahara H, Akagi A, Sone J, Urushitani M, Yoshida M, Iwasaki Y. Nuclear Expression of TDP-43 Is Linked with Morphology and Ubiquitylation of Cytoplasmic Aggregates in Amyotrophic Lateral Sclerosis. International Journal of Molecular Sciences. 2023; 24(15):12176. https://doi.org/10.3390/ijms241512176
Chicago/Turabian StyleYabata, Hiroyuki, Yuichi Riku, Hiroaki Miyahara, Akio Akagi, Jun Sone, Makoto Urushitani, Mari Yoshida, and Yasushi Iwasaki. 2023. "Nuclear Expression of TDP-43 Is Linked with Morphology and Ubiquitylation of Cytoplasmic Aggregates in Amyotrophic Lateral Sclerosis" International Journal of Molecular Sciences 24, no. 15: 12176. https://doi.org/10.3390/ijms241512176