Differential regulation of microtubule dynamics by three- and four-repeat tau: implications for the onset of neurodegenerative disease
Open accessAbstract
The microtubule (MT)-associated protein tau is important in neuronal development and in Alzheimer's and other neurodegenerative diseases. Genetic analyses have established a cause-and-effect relationship between tau dysfunction/misregulation and neuronal cell death and dementia in frontotemporal dementia and parkinsonism associated with chromosome 17; several mutations causing this dementia lead to increased ratios of four-repeat (4R) to three-repeat (3R) wild-type tau, and an attractive hypothesis is that the abnormally high ratio of 4R to 3R tau might lead to neuronal cell death by altering normal tau functions in adult neurons. Thus, we tested whether 3R and 4R tau might differentially modulate the dynamic instability of MTs in vitro using video microscopy. Although both isoforms promoted MT polymerization and decreased the tubulin critical subunit concentration to approximately similar extents, 4R tau stabilized MTs significantly more strongly that 3R tau. For example, 4R tau suppressed the shortening rate, whereas 3R tau had little or no detectable effect. Similarly, 3R tau had no effect on the length shortened during a shortening event, whereas 4R tau strongly reduced this parameter. Further, when MTs were diluted into buffer containing 4R tau, the MTs were stabilized and shortened slowly. In contrast, when diluted into 3R tau, the MTs were unstable and shortened rapidly. Thus, 4R tau stabilizes MTs differently and significantly more strongly than 3R tau. We suggest a “dosage effect” or haploinsufficiency model in which both tau alleles must be active and properly regulated to produce appropriate amounts of each tau isoform to maintain MT dynamics within a tolerable window of activity.
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Tau regulates the axonal cytoskeleton.
“Tau regulates the axonal cytoskeleton (Kanai et al., 1992; Chen et al., 1992; Panda et al., 2003; Rosenberg et al., 2008; Chung et al., 2015; Biswas and Kalil, 2018), and acts as a selective barrier on microtubules to direct intracellular transport”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Panda et al., 2003
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Beaudet, D., Berger, C. L., & Hendricks, A. G. (2026) · eLife · doi:10.7554/elife.110011
- Authors
- Panda, D., Samuel, J. C., Massie, M., Feinstein, S. C., & Wilson, L.
- Affiliations
- University of California, Santa Barbara (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2003-07-28
- Volume
- 100
- Issue
- 16
- Pages
- 9548-9553
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC170955
- OpenAlex
- W1971775491
- Cited by
- 280
- References
- 6
- Citations by year
- 2026: 13 · 2025: 13 · 2024: 17 · 2023: 9 · 2022: 19 · 2021: 9 · 2020: 13 · 2019: 15 · 2018: 11 · 2017: 15 · 2016: 13 · 2015: 12 · 2014: 11 · 2013: 14 · 2012: 14
- FWCI
- 4.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS-35010, NS 13560, R01NS035010, R01NS013560)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- tau protein, tau isoforms, microtubule dynamics, microtubule stabilization, microtubule assembly, critical concentration, microtubule shortening, frontotemporal dementia, Alzheimer's disease, neurodegeneration, haploinsufficiency, dosage effect, neuronal cell death
- MeSH terms
- Alleles, Animals, Cell Survival, Dose-Response Relationship, Drug, Escherichia coli, Gene Expression Regulation, Microtubules, Models, Genetic, Neurons, Recombinant Proteins, Time Factors, Tubulin, tau Proteins, Cell Death, Microscopy, Video, Protein Isoforms, Rats
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