Ftdp-17 Mutations Compromise the Ability of Tau to Regulate Microtubule Dynamics In Cells

Janis M. Bunker, Kathy Kamath, Leslie Wilson,
Mary Ann Jordan, and Stuart C. Feinstein
Neuroscience Research Institute and Department of Molecular, Cellular and Developmental
Biology, University of California, Santa Barbara, California 93106
Running Title: FTDP-17 Mutations Compromise Tau Function
Address correspondence to Dr. Stuart Feinstein, Neuroscience Research Institute, Bldg 571, Rm 6129,
University of California, Santa Barbara, CA 93106; Tel. (805) 893-2659; Fax. (805) 893-2659, Email:
feinstei [at] lifesci.ucsb.edu


The neural microtubule-associated protein tau binds directly to microtubules and regulates their dynamic behavior. In addition to being required for normal development, maintenance and function of the nervous system, tau is associated with several neurodegenerative diseases, including Alzheimer's disease. One group of neurodegenerative dementias known as FTDP- 17 (fronto-temporal dementia with Parkinsonism linked to chromosome 17) are directly linked genetically to mutations in the tau gene, demonstrating that tau misfunction can cause neuronal cell death and dementia. These mutations result either in amino-acid substitutions in tau, or in altered tau mRNA splicing that skews the expression ratio of wildtype 3-repeat and 4-repeat tau isoforms. Since wild-type tau regulates microtubule dynamics, one possible mechanism underlying taumediated neurodegeneration is aberrant regulation of microtubule behavior. In this study, we microinjected normal and mutated tau proteins into GFP-tubulin-expressing cultured cells and measured the effects on the dynamic instability of individual microtubules. We found that the FTDP-17 amino-acid substitutions G272V (in both 3-repeat and 4- repeat tau contexts), ΔK280, and P301L all exhibited markedly reduced abilities to regulate dynamic instability relative to wild-type tau. In contrast, the FTDP-17 R406W mutation (which maps in a regulatory region outside the microtubule binding domain of tau) did not significantly alter the ability of 3-repeat or 4- repeat tau to regulate microtubule dynamics. Overall, these data are consistent with a loss-offunction model in which both amino-acid substitutions and altered mRNA-splicing in tau lead to neurodegeneration by diminishing the ability of tau to properly regulate microtubule dynamics.
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Janis M. Bunker, Kathy Kamath, Leslie Wilson, Mary Ann Jordan, and Stuart C. Feinstein,
The Journal of Biological Chemistry, 2006.
Node ID: 209 , DB ID: 230 , Lab: BIO , Target: Journal