Journal article
Strategies for diminishing katanin-based loss of microtubules in tauopathic neurodegenerative diseases
Human molecular genetics, v 20(4), pp 763-778
15 Feb 2011
PMID: 21118899
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- Strategies for diminishing katanin-based loss of microtubules in tauopathic neurodegenerative diseases
- Creators
- Haruka Sudo - ,Peter W Baas - ,
- Publication Details
- Human molecular genetics, v 20(4), pp 763-778
- Publisher
- Oxford University Press
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Web of Science ID
- WOS:000286469400012
- Scopus ID
- 2-s2.0-78751685767
- Other Identifier
- 991014878105704721
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- Web of Science research areas
- Biochemistry & Molecular Biology
- Genetics & Heredity