Suppressing Tau Aggregation and Toxicity by an Anti-Aggregant Tau Fragment.

Autor: Pir GJ; German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 27, 53127, Bonn, Germany. Jeelani.Pir@dzne.de.; Max-Planck-Institute for Metabolism Research, Hamburg Outstation, c/o DESY, Notkestrasse 85, 22607, Hamburg, Germany. Jeelani.Pir@dzne.de., Choudhary B; German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 27, 53127, Bonn, Germany.; Max-Planck-Institute for Metabolism Research, Hamburg Outstation, c/o DESY, Notkestrasse 85, 22607, Hamburg, Germany., Kaniyappan S; German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 27, 53127, Bonn, Germany.; Max-Planck-Institute for Metabolism Research, Hamburg Outstation, c/o DESY, Notkestrasse 85, 22607, Hamburg, Germany., Chandupatla RR; German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 27, 53127, Bonn, Germany.; Max-Planck-Institute for Metabolism Research, Hamburg Outstation, c/o DESY, Notkestrasse 85, 22607, Hamburg, Germany., Mandelkow E; German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 27, 53127, Bonn, Germany.; Max-Planck-Institute for Metabolism Research, Hamburg Outstation, c/o DESY, Notkestrasse 85, 22607, Hamburg, Germany.; CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175, Bonn, Germany., Mandelkow EM; German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 27, 53127, Bonn, Germany. Eva.Mandelkow@dzne.de.; Max-Planck-Institute for Metabolism Research, Hamburg Outstation, c/o DESY, Notkestrasse 85, 22607, Hamburg, Germany. Eva.Mandelkow@dzne.de.; CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175, Bonn, Germany. Eva.Mandelkow@dzne.de., Wang Y; German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 27, 53127, Bonn, Germany. yipeng810@qq.com.; Max-Planck-Institute for Metabolism Research, Hamburg Outstation, c/o DESY, Notkestrasse 85, 22607, Hamburg, Germany. yipeng810@qq.com.
Jazyk: angličtina
Zdroj: Molecular neurobiology [Mol Neurobiol] 2019 May; Vol. 56 (5), pp. 3751-3767. Date of Electronic Publication: 2018 Sep 08.
DOI: 10.1007/s12035-018-1326-z
Abstrakt: Tau aggregation is a hallmark of a group of neurodegenerative diseases termed Tauopathies. Reduction of aggregation-prone Tau has emerged as a promising therapeutic approach. Here, we show that an anti-aggregant Tau fragment (F3 ΔKPP , residues 258-360) harboring the ΔK280 mutation and two proline substitutions (I 277 P & I 308 P) in the repeat domain can inhibit aggregation of Tau constructs in vitro, in cultured cells and in vivo in a Caenorhabditis elegans model of Tau aggregation. The Tau fragment reduced Tau-dependent cytotoxicity in a N2a cell model, suppressed the Tau-mediated neuronal dysfunction and ameliorated the defective locomotion in C. elegans. In vitro the fragment competes with full-length Tau for polyanionic aggregation inducers and thus inhibits Tau aggregation. Our combined in vitro and in vivo results suggest that the anti-aggregant Tau fragment may potentially be used to address the consequences of Tau aggregation in Tauopathies.
Databáze: MEDLINE
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