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Cited by 134Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Phosphorylation in the amino terminus of tau prevents inhibition of anterograde axonal transport

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Kanaan, Nicholas M., Morfini, Gerardo, Pigino, Gustavo, LaPointe, Nichole E., Andreadis, Athena, Song, Yuyu, Leitman, Ellen, Binder, Lester I. +1 more·2012·Neurobiology of Aging
DOI 10.1016/j.neurobiolaging.2011.06.006PMC PMC3272324
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Abstract

Alzheimer's disease (AD) and other tauopathies are characterized by fibrillar inclusions composed of the microtubule-associated protein, tau. Recently, we demonstrated that the N-terminus of tau (amino acids [aa] 2-18) in filamentous aggregates or N-terminal tau isoforms activate a signaling cascade involving protein phosphatase 1 and glycogen synthase kinase 3 that results in inhibition of anterograde fast axonal transport (FAT). We have termed the functional motif comprised of aa 2-18 in tau the phosphatase-activating domain (PAD). Here, we show that phosphorylation of tau at tyrosine 18, which is a fyn phosphorylation site within PAD, prevents inhibition of anterograde FAT induced by both filamentous tau and 6D tau. Moreover, Fyn-mediated phosphorylation of tyrosine 18 is reduced in disease-associated forms of tau (e.g., tau filaments). A novel PAD-specific monoclonal antibody revealed that exposure of PAD in tau occurs before and more frequently than tyrosine 18 phosphorylation in the evolution of tangle formation in AD. These results indicate that N-terminal phosphorylation may constitute a regulatory mechanism that controls tau-mediated inhibition of anterograde FAT in AD.

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  • Mutations at Y18 increase tau dynamics on microtubules, reduce tau accumulation, and impair tau-mediated regulation of intracellular transport.

    “mutations at Y18, the terminal residue of PAD, increase tau dynamics on microtubules, reduce tau accumulation, and impair tau-mediated regulation of intracellular transport”

    From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Kanaan et al., 2012

    Results §3.2 reports that phosphorylation at Y18 prevents tau filaments from inhibiting fast axonal transport, supporting the transport portion of the claim. The cited passages do not show that mutations at Y18 increase tau dynamics on microtubules or reduce tau accumulation; the paper tests Y18 phosphorylation rather than establishing those effects of Y18 mutations. No page numbers are available in our copy. (LLM, conf=0.85)

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Authors
Kanaan, N. M., Morfini, G., Pigino, G., LaPointe, N. E., Andreadis, A., Song, Y., Leitman, E., Binder, L. I., & Brady, S. T.
Affiliations
  • Michigan State University (US)
  • Marine Biological Laboratory (US)
  • University of California, Santa Barbara (US)
  • University of Massachusetts Chan Medical School (US)
  • Northwestern University (US)
ORCID
Venue
Neurobiology of Aging
Publisher
Elsevier BV
Published
2012-04
Volume
33
Issue
4
Pages
826.e15-826.e30
ISSN
0197-4580 (ISSN-L)
DOI
10.1016/j.neurobiolaging.2011.06.006
PMC
PMC3272324
OpenAlex
W1965957039
Cited by
134
References
5
Citations by year
2026: 9 · 2025: 5 · 2024: 4 · 2023: 11 · 2022: 6 · 2021: 11 · 2020: 11 · 2019: 15 · 2018: 9 · 2017: 14 · 2016: 11 · 2015: 9 · 2014: 8 · 2013: 7 · 2012: 3
FWCI
3.92
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Neurobiology of Aging (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship@UMassChan (submittedVersion)
Funders
  • NIH (T32 AG020506-07, AG09466, NS23868, NS23320, NS41170, R01 NS066942A)
  • ALS/CVS Therapy Alliance
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
tau phosphorylation, anterograde axonal transport, fast axonal transport, Alzheimer's disease, tauopathy, Fyn, protein phosphatase 1, glycogen synthase kinase-3, tau filaments, tau tangles, monoclonal antibodies
MeSH terms
Alzheimer Disease, Analysis of Variance, Animals, Axonal Transport, Brain, Enzyme-Linked Immunosorbent Assay, Humans, Mutation, Neural Inhibition, Phosphorylation, Time Factors, Tyrosine, Signal Transduction, tau Proteins, Protein Isoforms, Decapodiformes, Proto-Oncogene Proteins c-fyn, Protein Interaction Domains and Motifs

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