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Asparagine residue 368 is involved in Alzheimer’s disease tau strain‐specific aggregation
Author(s) -
Shimonaka Shotaro,
Elahi Montasir,
Matsumoto ShinEi,
Ishiguro Koichi,
Hasegawa Masato,
Hattori Nobutaka,
Motoi Yumiko
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.047498
Subject(s) - progressive supranuclear palsy , corticobasal degeneration , tauopathy , fibril , tau protein , mutant , chemistry , protein aggregation , mutagenesis , biochemistry , biophysics , biology , neurodegeneration , alzheimer's disease , genetics , disease , medicine , pathology , gene , atrophy
Background In tauopathies, tau forms pathogenic fibrils with distinct conformations (termed ‘tau strains’) and acts as an aggregation “seed” promoting the conversion of normal tau into isomorphic fibrils. Previous research showed that the aggregation core of tau fibril covers the carboxy‐terminal region (243–406) and differs among the diseases. However, the mechanisms by which distinct fibrous structures are formed and inherited in comparison to normal tau via templated aggregation are still unknown. Here, we sought to identify the key sequences of seed‐dependent aggregation. Method To identify sequences for which deletion reduces tau aggregation, SH‐SY5Y cells expressing a series of 10 partial deletion (Del 1–10, covering 244–400 aa) mutants of tau‐CTF24 (243–441 aa) were treated with tau seeds prepared from a different tauopathy patient’s brain [Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD)] or recombinant tau and then, seed‐dependent tau aggregation was assessed biochemically. Furthermore, we systematically repeated cellular tau aggregation assays for the delineation of shorter deletion sites to identify the minimum sequence responsible for tau aggregation. Result We found that the Del 8 mutant lacking 353–368 aa showed significantly decreased aggregation in both cellular and in vitro models. Mutagenesis studies revealed that Asn368 mutation suppressed tau aggregation triggered by an AD‐tau seed, but not using other tauopathies seeds, including PSP and CBD. Similar effects were also observed with Ala replacement of the Ser320 residue, which was arranged facing inwards toward Asn368, in the AD‐tau core structure that was determined recently by means of cryo‐electron microscopy. Conclusion Our study suggested that 353–368 aa is a novel aggregation‐responsible sequence other than PHF6 and PHF6*, and within this sequence, the Asn368 residue plays a role in strain‐specific tau aggregation in different tauopathies, possibly along with Ser320.