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Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Hasegawa M, Arai T, Nonaka T, Kametani F, Yoshida M, Hashizume Y, Beach TG, Buratti E et al.. Annals of neurology, 2008-07-01
Topic: Brain proteins, microglia and lab models
Objective TAR DNA-binding protein of 43kDa (TDP-43) is deposited as cytoplasmic and intranuclear inclusions in brains of patients with frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Previous studies reported that abnormal phosphorylation takes place in deposited TDP-43. The aim of this study was to identify the phosphorylation sites and responsible kinases, and to clarify the pathological significance of phosphorylation of TDP-43. Methods We generated multiple antibodies specific to phosphorylated TDP-43 by immunizing phosphopeptides of TDP-43, and analyzed FTLD-U and ALS brains by immunohistochemistry, immunoelectron microscopy, and immunoblots. In addition, we performed investigations aimed at identifying the responsible kinases, and we assessed the effects of phosphorylation on TDP-43 oligomerization and fibrillization. Results We identified multiple phosphorylation sites in carboxyl-terminal regions of deposited TDP-43. Phosphorylation-specific antibodies stained more inclusions than antibodies to ubiquitin and, unlike existing commercially available anti-TDP-43 antibodies, did not stain normal nuclei. Ultrastructurally, these antibodies labeled abnormal fibers of 15nm diameter and on immunoblots recognized hyperphosphorylated TDP-43 at 45kDa, with additional 18 to 26kDa fragments in sarkosyl-insoluble fractions from FTLD-U and ALS brains. The phosphorylated epitopes were generated by casein kinase-1 and -2, and phosphorylation led to increased oligomerization and fibrillization of TDP-43. Interpretation These results suggest that phosphorylated TDP-43 is a major component of the inclusions, and that abnormal phosphorylation of TDP-43 is a critical step in the pathogenesis of FTLD-U and ALS. Phosphorylation-specific antibodies will be powerful tools for the investigation of these disorders.
Key findings
- Results We identified multiple phosphorylation sites in carboxyl-terminal regions of deposited TDP-43.
- Interpretation These results suggest that phosphorylated TDP-43 is a major component of the inclusions, and that abnormal phosphorylation of TDP-43 is a critical step in the pathogenesis of FTLD-U and ALS.
Why it matters
This laboratory study of post-mortem brain tissue from people with frontotemporal lobar degeneration (FTLD-U) and ALS made antibodies that recognise only the phosphorylated (chemically tagged) form of the protein TDP-43; they stained more of the disease inclusions than ubiquitin antibodies and, unlike commercial TDP-43 antibodies, did not stain normal cell nuclei. The tags sat in the protein's tail end, were added by the enzymes casein kinase-1 and -2, and increased TDP-43 clumping in the authors' experiments, leading them to suggest that abnormal phosphorylation is "a critical step" in FTLD-U and ALS. It does not study Alzheimer's disease or living patients, gives no case numbers, and tests no treatment.
Study details
- Evidence strengthLow
How this study scored 54/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Annals of neurology) |
| Journal's citation record | 3 / 4 | Annals of Neurology: journal h-index 437 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2008 — within 20 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 783 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 39.1 citations a year over 20 year(s) since 2008 |
| Impact for its field and year | 5 / 6 | Cited 28.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 44 other studies in this library |
| Still being cited | 3 / 4 | Cited 147 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Haruhiko Akiyama: h-index 101 (OpenAlex, whole career) |
| Institution's track record | 0 / 3 | Jichi Medical University: institution h-index 428 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 5 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 18546284) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 54 / 100 | — |
What each of these 20 components measures, and what this score is not →
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APA 7th
Hasegawa, M., Arai, T., Nonaka, T., Kametani, F., Yoshida, M., Hashizume, Y., et al. (2008). Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Annals of neurology. https://doi.org/10.1002/ana.21425
Vancouver
Hasegawa M, Arai T, Nonaka T, Kametani F, Yoshida M, Hashizume Y, et al. Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Annals of neurology. 2008. doi:10.1002/ana.21425. PMID: 18546284.
BibTeX
@article{hasegawa2008-18546284,
author = {Hasegawa, M. and Arai, T. and Nonaka, T. and Kametani, F. and Yoshida, M. and Hashizume, Y. and Beach, T. G. and Buratti, E. and others},
title = {{Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis}},
journal = {Annals of neurology},
year = {2008},
doi = {10.1002/ana.21425},
pmid = {18546284},
url = {https://doi.org/10.1002/ana.21425}
}
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