Familial FTDP-17 Missense Mutations Inhibit Microtubule Assembly-promoting Activity of Tau by Increasing Phosphorylation at Ser202 in Vitro
Open accessAbstract
In Alzheimer disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and other tauopathies, tau accumulates and forms paired helical filaments (PHFs) in the brain. Tau isolated from PHFs is phosphorylated at a number of sites, migrates as approximately 60-, 64-, and 68-kDa bands on SDS-gel, and does not promote microtubule assembly. Upon dephosphorylation, the PHF-tau migrates as approximately 50-60-kDa bands on SDS-gels in a manner similar to tau that is isolated from normal brain and promotes microtubule assembly. The site(s) that inhibits microtubule assembly-promoting activity when phosphorylated in the diseased brain is not known. In this study, when tau was phosphorylated by Cdk5 in vitro, its mobility shifted from approximately 60-kDa bands to approximately 64- and 68-kDa bands in a time-dependent manner. This mobility shift correlated with phosphorylation at Ser(202), and Ser(202) phosphorylation inhibited tau microtubule-assembly promoting activity. When several tau point mutants were analyzed, G272V, P301L, V337M, and R406W mutations associated with FTDP-17, but not nonspecific mutations S214A and S262A, promoted Ser(202) phosphorylation and mobility shift to a approximately 68-kDa band. Furthermore, Ser(202) phosphorylation inhibited the microtubule assembly-promoting activity of FTDP-17 mutants more than of WT. Our data indicate that FTDP-17 missense mutations, by promoting phosphorylation at Ser(202), inhibit the microtubule assembly-promoting activity of tau in vitro, suggesting that Ser(202) phosphorylation plays a major role in the development of NFT pathology in AD and related tauopathies.
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Tau phosphorylation at S202/T205 as detected by the AT8 antibody is commonly found in tauopathies.
“Tau phosphorylation at S202/T205 as detected by the AT8 antibody (80) is commonly found in tauopathies (38,81–84).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [84]
The Discussion (page unavailable) reports strong AT8 staining in Alzheimer’s disease and Ser202 phosphorylation recognized by AT8 in FTDP-17 brains. This supports AT8-detected Ser202 phosphorylation in those conditions, but the copy does not establish Thr205 phosphorylation or its prevalence across tauopathies. (LLM, conf=0.86)
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Self-citationPiericidin A Aggravates Tau Pathology in P301S Transgenic Mice
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Hypoxic ischemia and proteasome dysfunction alter tau isoform ratio by inhibiting exon 10 splicing
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HS3ST2 expression induces the cell autonomous aggregation of tau
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- Authors
- Han, D., Qureshi, H. Y., Lu, Y., & Paudel, H. K.
- Affiliations
- Jewish General Hospital (CA)
- Corresponding author
- Paudel, Hemant K.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-05
- Volume
- 284
- Issue
- 20
- Pages
- 13422-13433
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2679442
- OpenAlex
- W2018823212
- Cited by
- 40
- References
- 54
- Citations by year
- 2025: 2 · 2022: 4 · 2020: 2 · 2018: 3 · 2016: 1 · 2015: 3 · 2014: 6 · 2013: 6 · 2012: 4
- FWCI
- 2.88
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer Society
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- FTDP-17, tau phosphorylation, microtubule assembly, tauopathy, Alzheimer's disease, frontotemporal dementia, paired helical filaments, cyclin-dependent kinase 5, missense mutations, neurofibrillary tangles, tau dephosphorylation
- MeSH terms
- Animals, Cattle, Chromosomes, Human, Pair 17, Humans, Microtubules, Phosphorylation, tau Proteins, Mutation, Missense, Tauopathies, Cyclin-Dependent Kinase 5
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