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Cited by 142Alzheimer's disease research and treatmentsMitochondrial Function and PathologyNeuroinflammation and Neurodegeneration Mechanisms

Loss of Axonal Mitochondria Promotes Tau-Mediated Neurodegeneration and Alzheimer's Disease–Related Tau Phosphorylation Via PAR-1

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Iijima-Ando, Kanae, Sekiya, Michiko, Maruko-Otake, Akiko, Ohtake, Yosuke, Suzuki, Emiko, Lu, Bingwei, Iijima, Koichi M.·2012·PLoS Genetics
DOI 10.1371/journal.pgen.1002918PMC PMC3431335
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Abstract

Abnormal phosphorylation and toxicity of a microtubule-associated protein tau are involved in the pathogenesis of Alzheimer's disease (AD); however, what pathological conditions trigger tau abnormality in AD is not fully understood. A reduction in the number of mitochondria in the axon has been implicated in AD. In this study, we investigated whether and how loss of axonal mitochondria promotes tau phosphorylation and toxicity in vivo. Using transgenic Drosophila expressing human tau, we found that RNAi-mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD-related site Ser262 increased with knockdown of milton or Miro; and partitioning defective-1 (PAR-1), the Drosophila homolog of mammalian microtubule affinity-regulating kinase, mediated this increase of tau phosphorylation. Tau phosphorylation at Ser262 has been reported to promote tau detachment from microtubules, and we found that the levels of microtubule-unbound free tau increased by milton knockdown. Blocking tau phosphorylation at Ser262 site by PAR-1 knockdown or by mutating the Ser262 site to unphosphorylatable alanine suppressed the enhancement of tau-induced neurodegeneration caused by milton knockdown. Furthermore, knockdown of milton or Miro increased the levels of active PAR-1. These results suggest that an increase in tau phosphorylation at Ser262 through PAR-1 contributes to tau-mediated neurodegeneration under a pathological condition in which axonal mitochondria is depleted. Intriguingly, we found that knockdown of milton or Miro alone caused late-onset neurodegeneration in the fly brain, and this neurodegeneration could be suppressed by knockdown of Drosophila tau or PAR-1. Our results suggest that loss of axonal mitochondria may play an important role in tau phosphorylation and toxicity in the pathogenesis of AD.

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Authors
Iijima-Ando, K., Sekiya, M., Maruko-Otake, A., Ohtake, Y., Suzuki, E., Lu, B., & Iijima, K. M.
Affiliations
  • Thomas Jefferson University (US)
  • National Institute of Genetics (JP)
  • Stanford Medicine (US)
Corresponding author
Iijima, Koichi M.
ORCID
Venue
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Published
2012-08-30
Volume
8
Issue
8
Pages
e1002918
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1002918
PMC
PMC3431335
OpenAlex
W2001410029
Cited by
142
References
11
Citations by year
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FWCI
7.04
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • The Medicine Forum (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • Alzheimer's Association (NIRG-08-91985)
  • Thomas Jefferson University
  • Uehara Memorial Foundation
  • National Institutes of Health
  • National Institute on Aging (R01AG032279)
  • National Institute of General Medical Sciences (R01GM084947, GM084947)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
axonal mitochondria, tau phosphorylation, tauopathy, Alzheimer's disease, protease-activated receptor 1, John Milton, Miro, microtubule binding, neurodegeneration, Drosophila model
MeSH terms
Alzheimer Disease, Animals, Axons, Drosophila, Humans, Microtubules, Mitochondria, Nerve Degeneration, Phosphorylation, tau Proteins, rho GTP-Binding Proteins, Drosophila Proteins, Animals, Genetically Modified, Glycogen Synthase Kinase 3, Gene Knockdown Techniques

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