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Strategies for diminishing katanin-based loss of microtubules in tauopathic neurodegenerative diseases.

Abstract
It is commonly stated that microtubules gradually disintegrate as tau becomes dissociated from them in tauopathies such as Alzheimer's disease. However, there has been no compelling evidence to date that such disintegration is due to depolymerization of microtubules from their ends. In recent studies, we have shown that neurons contain sufficient levels of the microtubule-severing protein termed katanin to completely break down the axonal microtubule array if not somehow attenuated. The presence of tau on axonal microtubules renders them notably less sensitive to katanin, prompting us to posit that microtubule disintegration in tauopathies may result from elevated severing of the microtubules as they lose tau. In support of this hypothesis, we demonstrate here that pathogenic tau mutants that bind less strongly to microtubules than wild-type tau provide correspondingly less protection against katanin-based severing. Using cultured rat hippocampal neurons, we pursued two potential therapies for fortifying axonal microtubules against excess severing by katanin, under conditions of tau depletion. We found that either deacetylating the microtubules via overexpression of HDAC6 or treating the neurons with NAP, a microtubule-interacting neuroprotective peptide, resulted in notable protection of the microtubules against katanin-based loss. In both cases, we found that these treatments also diminished the characteristic increase in axonal branching that normally accompanies tau depletion, an effect that is also known to be directly related to the severing of microtubules. These observations may be useful in developing therapeutic regimes for preserving microtubules against loss in the axons of patients suffering from tauopathies.
AuthorsHaruka Sudo, Peter W Baas
JournalHuman molecular genetics (Hum Mol Genet) Vol. 20 Issue 4 Pg. 763-78 (Feb 15 2011) ISSN: 1460-2083 [Electronic] England
PMID21118899 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Mutant Proteins
  • Oligopeptides
  • Tubulin
  • tau Proteins
  • HDAC6 protein, rat
  • Histone Deacetylase 6
  • Histone Deacetylases
  • Adenosine Triphosphatases
  • Katanin
  • davunetide
Topics
  • Adenosine Triphosphatases (metabolism)
  • Animals
  • Cell Line
  • Gene Expression Regulation
  • Hippocampus (cytology, metabolism)
  • Histone Deacetylase 6
  • Histone Deacetylases (genetics, metabolism)
  • Humans
  • Katanin
  • Microtubules (metabolism)
  • Mutant Proteins (genetics, metabolism)
  • Neurons (metabolism)
  • Oligopeptides (metabolism, pharmacology)
  • RNA Interference
  • Rats
  • Tauopathies (metabolism, pathology)
  • Tubulin (genetics, metabolism)
  • tau Proteins (genetics, metabolism)

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