Bunker_et_al_JBC - FTDP-17 Mutations Compromise the Ability...

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Unformatted text preview: FTDP-17 Mutations Compromise the Ability of Tau to Regulate Microtubule Dynamics in Cells * S Received for publication, August 25, 2005, and in revised form, February 21, 2006 Published, JBC Papers in Press, February 21, 2006, DOI 10.1074/jbc.M509420200 Janis M. Bunker, Kathy Kamath, Leslie Wilson, Mary Ann Jordan, and Stuart C. Feinstein 1 From the Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, California 93106 The neural microtubule-associated protein Tau binds directly to microtubules and regulates their dynamic behavior. In addi- tion to being required for normal development, maintenance, and function of the nervous system, Tau is associated with sev- eral neurodegenerative diseases, including Alzheimer disease. One group of neurodegenerative dementias known as FTDP-17 (fronto- temporal dementia with Parkinsonism linked to chromosome 17) is directly linked genetically to mutations in the tau gene, demon- strating 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 wild-type 3-repeat and 4-repeat Tau isoforms. Because wild-type Tau regulates microtubule dynamics, one possible mech- anism underlying Tau-mediated neurodegeneration is aberrant regulation of microtubule behavior. In this study, we microinjected normal and mutated Tau protein into cultured cells expressing flu- orescent tubulin and measured the effects on the dynamic instabil- ity of individual microtubules. We found that the FTDP-17 amino acid substitutions G272V (in both 3-repeat and 4-repeat Tau con- texts), K280,andP301Lallexhibitedmarkedlyreducedabilitiesto 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 reg- ulate microtubule dynamics. Overall, these data are consistent with a loss-of-function model in which both amino acid substi- tutions and altered mRNA splicing in Tau lead to neurodegen- eration by diminishing the ability of Tau to properly regulate microtubule dynamics. Microtubules are dynamic polymers with growing and shortening behaviors that are exquisitely regulated. The dynamic behaviors of microtubules are both temporally and spatially regulated, even within individual cells (1). For example, microtubule dynamics in migrating cells differ at the leading and trailing edges (2). The role of microtubule dynamics is best understood in the processes of mitosis and cell division, where microtubules play central roles in spindle assembly, the metaphase/anaphase checkpoint, and chromo- some segregation (35). Microtubule dynamics are also essential in post-mitotic neurons, serving critical roles in establishing cell polarity, axon outgrowth, cell signaling, adhesion, the organization of cellular...
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Bunker_et_al_JBC - FTDP-17 Mutations Compromise the Ability...

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