Differential effect of three-repeat and four-repeat tau on mitochondrial axonal transport

J Neurochem. 2009 Oct;111(2):417-27. doi: 10.1111/j.1471-4159.2009.06316.x. Epub 2009 Aug 3.

Abstract

Tau protein is present in six different splice forms in the human brain and interacts with microtubules via either 3 or 4 microtubule binding repeats. An increased ratio of 3 repeat to 4 repeat isoforms is associated with neurodegeneration in inherited forms of frontotemporal dementia. Tau over-expression diminishes axonal transport in several systems, but differential effects of 3 repeat and 4 repeat isoforms have not been studied. We examined the effects of tau on mitochondrial transport and found that both 3 repeat and 4 repeat tau change normal mitochondrial distribution within the cell body and reduce mitochondrial localization to axons; 4 repeat tau has a greater effect than 3 repeat tau. Further, we observed that the 3 repeat and 4 repeat tau cause different alterations in retrograde and anterograde transport dynamics with 3 repeat tau having a slightly stronger effect on axon transport dynamics. Our results indicate that tau-induced changes in axonal transport may be an underlying theme in neurodegenerative diseases associated with isoform specific changes in tau's interaction with microtubules.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Axonal Transport / physiology*
  • Cell Line, Tumor
  • Cerebral Cortex / cytology
  • Glioma
  • Green Fluorescent Proteins / genetics
  • Humans
  • Mice
  • Microfluidic Analytical Techniques
  • Mitochondria / physiology*
  • Neurons / cytology
  • Neurons / physiology*
  • Protein Transport / physiology
  • Repetitive Sequences, Nucleic Acid / physiology
  • Tauopathies / genetics
  • Tauopathies / metabolism
  • Tauopathies / physiopathology*
  • Transfection
  • tau Proteins / genetics*
  • tau Proteins / metabolism*

Substances

  • MAPT protein, human
  • tau Proteins
  • Green Fluorescent Proteins