Phosphorylated TDP‐43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Open accessAbstract
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.
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GSK-3β has not been identified as a kinase of TDP-43, even when specifically tested for TDP-43 phosphorylation.
“GSK-3β has not been identified as a kinase of TDP-43, even when specifically tested for TDP-43 phosphorylation (102)”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [102]
The Methods describe an in vitro test of GSK3β on TDP-43. In the Results section, TDP-43 treated with GSK3β was negative with the study’s phosphorylation-specific antibodies. That supports a negative result for the epitopes tested, but not the broader assertion that GSK3β has not been identified as a TDP-43 kinase at any site. (LLM, conf=0.85)
Experimental — accuracy not yet measuredTDP-43 can be phosphorylated, which is hypothesized to play a role in its toxicity.
“TDP-43 can be phosphorylated, which is hypothesized to play a role in its toxicity (102,103).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [102]
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- Authors
- Hasegawa, M., Arai, T., Nonaka, T., Kametani, F., Yoshida, M., Hashizume, Y., Beach, T. G., Buratti, E., Baralle, F., Morita, M., Nakano, I., Oda, T., Tsuchiya, K., & Akiyama, H.
- Affiliations
- Tokyo Institute of Psychiatry (JP)
- Aichi Medical University (JP)
- International Centre for Genetic Engineering and Biotechnology (IT)
- Jichi Medical University (JP)
- Tokyo Metropolitan Matsuzawa Hospital (JP)
- Corresponding author
- Hasegawa, Masato
- Arai, Tetsuaki
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2008-06-10
- Volume
- 64
- Issue
- 1
- Pages
- 60-70
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC2674108
- OpenAlex
- W2041451000
- Cited by
- 777
- References
- 1
- Citations by year
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- FWCI
- 30.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (P30-AG-19610, P30AG019610)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- TDP-43, phosphorylation, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, casein kinase 1, casein kinase 2, ubiquitinated inclusions
- MeSH terms
- Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, Antibodies, Antibody Specificity, Epitopes, Brain, Inclusion Bodies, Dementia, DNA-Binding Proteins, Female, Humans, Male, Middle Aged, Peptide Fragments, Phosphorylation, Neurofibrillary Tangles, Protein Structure, Tertiary, Casein Kinase I
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