title: Identification of key amino acids responsible for the distinct aggregation properties of microtubule-associated protein 2 and tau.
abstract: The carboxyl-terminal sequence of tau composes the framework for its intracellular inclusions that appear in diverse neurodegenerative disorders known as tauopathies. However, microtubule-associated protein 2 (MAP2), which contains a homologous carboxyl-terminal sequence of tau, is undetectable in the mature tau inclusions. The mechanisms underlying this phenomenon have remained largely unknown. Here, we show that tau and MAP2 have different aggregation properties: tau aggregates to form filaments but MAP2 remains to be granules. Exchanging (221) YKPV(224) of tau (0N3R) near the PHF6 motif for (340) TKKI(343) of MAP2c profoundly changed aggregation properties, suggesting that the YKPV motif is important for filament formation, whereas the TKKI motif is for granule formation. Thus, these minimal sequences may determine the different fates of tau and MAP2 in the formation of inclusions in tauopathies. Tau and microtubule-associated protein 2 (MAP2) are homologous microtubule-associated proteins in neurons. So far, it is largely unknown why tau but not MAP2 is selectively involved in the filamentous inclusions (neurofibrillary tangles, NFT) formation in tauopathies, including Alzheimer's disease. In this study, we found that the difference of only two amino acids in tau and MAP2 sequences may determine their different fates in tauopathies. These results may lead to the elucidation of tau deregulation in pathological conditions.
authors.affiliation: Key Laboratory for Cellular and Molecular Biology of Liaoning Province, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China.|Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan.
authors.forename: Ce
authors.initials: C
authors.lastname: Xie
authors.affiliation: Department of Aging Neurobiology, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Soeda
authors.affiliation: Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Shinzaki
authors.affiliation: Department of Physical Chemistry, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: In
authors.affiliation: Department of Physical Chemistry, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Tomoo
authors.affiliation: Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ihara
authors.affiliation: Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Miyasaka
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D016874:Neurofibrillary Tangles / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D024801:Tauopathies / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D000596:Amino Acids; C489788:MAP2 protein, human; C054369:MAPT protein, human; D008869:Microtubule-Associated Proteins; D016875:tau Proteins
keywords: MAP2; aggregation; inclusion; microtubule-associated protein 2; tau; tauopathies