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Cited by 236Microtubule and mitosis dynamicsAlzheimer's disease research and treatmentsHereditary Neurological Disorders

MARK/PAR1 kinase is a regulator of microtubule-dependent transport in axons

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Mandelkow, Eva-Maria, Thies, Edda, Trinczek, Bernhard, Biernat, Jacek, Mandelkow, Eckard·2004·The Journal of Cell Biology
DOI 10.1083/jcb.200401085PMC PMC2172520
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Abstract

Microtubule-dependent transport of vesicles and organelles appears saltatory because particles switch between periods of rest, random Brownian motion, and active transport. The transport can be regulated through motor proteins, cargo adaptors, or microtubule tracks. We report here a mechanism whereby microtubule associated proteins (MAPs) represent obstacles to motors which can be regulated by microtubule affinity regulating kinase (MARK)/Par-1, a family of kinases that is known for its involvement in establishing cell polarity and in phosphorylating tau protein during Alzheimer neurodegeneration. Expression of MARK causes the phosphorylation of MAPs at their KXGS motifs, thereby detaching MAPs from the microtubules and thus facilitating the transport of particles. This occurs without impairing the intrinsic activity of motors because the velocity during active movement remains unchanged. In primary retinal ganglion cells, transfection with tau leads to the inhibition of axonal transport of mitochondria, APP vesicles, and other cell components which leads to starvation of axons and vulnerability against stress. This transport inhibition can be rescued by phosphorylating tau with MARK.

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  • Overexpression of Tau WT, 3A, or 3D reduced anterograde movement of mitochondria in PC12 cells and cortical neurons.

    “Overexpression of either Tau WT, 3A, or 3D reduced anterograde movement of mitochondria in PC12 cells and cortical neurons, as reported (Mandelkow et al., 2004;Hollenbeck and Saxton, 2005;Dixit et al., 2008).”

    From Regulation of Mitochondrial Transport and Inter-Microtubule Spacing by Tau Phosphorylation at the Sites Hyperphosphorylated in Alzheimer's Disease (2012) · cites this paper as Mandelkow et al., 2004

    The Results (Fig. 5; page unavailable) show that tau expression reduced anterograde mitochondrial movement in retinal ganglion cell axons, and Fig. 7 reports transport inhibition by a non-phosphorylatable tau mutant. The paper does not establish the stated effect for Tau 3D or in PC12 cells and cortical neurons; its experiments here use retinal ganglion cells and a KXGA mutant. (LLM, conf=0.88)

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Authors
Mandelkow, E.-M., Thies, E., Trinczek, B., Biernat, J., & Mandelkow, E.
Affiliations
Max Planck Unit for Structural Molecular Biology (DE)
ORCID
Venue
The Journal of Cell Biology
Publisher
Rockefeller University Press
Published
2004-10-04
Volume
167
Issue
1
Pages
99-110
ISSN
  • 0021-9525 (ISSN-L)
  • 1540-8140
DOI
10.1083/jcb.200401085
PMC
PMC2172520
OpenAlex
W2124922792
Cited by
236
References
4
Citations by year
2026: 4 · 2025: 3 · 2024: 3 · 2023: 7 · 2022: 1 · 2021: 6 · 2020: 7 · 2019: 6 · 2018: 8 · 2017: 14 · 2016: 11 · 2015: 6 · 2014: 10 · 2013: 11 · 2012: 21
FWCI
6.96
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of Cell Biology (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • DESY Publication Database (PUBDB) (Deutsches Elektronen-Synchrotron) (submittedVersion)
  • Max Planck Institute for Plasma Physics (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Keywords
MARK kinases, microtubule transport, axonal transport, microtubule-associated proteins, tau phosphorylation, retinal ganglion cells, cell polarity
MeSH terms
Adenoviridae, Animals, Axons, Biological Transport, Cricetinae, Humans, Microscopy, Fluorescence, Microtubules, Mitochondria, Models, Biological, Phosphorylation, Plasmids, Time Factors, Transfection, CHO Cells, tau Proteins, Protein Serine-Threonine Kinases, Amino Acid Motifs

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