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The role of tau-interacting protein in regulation of tau protein aggregations
- Author(s)
- 김수민
- Alternative Author(s)
- Sue Min Kim
- Advisor
- 박선아
- Department
- 일반대학원 의생명과학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2021-08
- Language
- eng
- Keyword
- Aggregation; Seeding; Sequestosome-1; Tau; p62
- Alternative Abstract
- The accumulation and aggregation of tau are hallmark pathology of Alzheimer’s disease (AD). In physiological condition tau binds to microtubules and supports their functions. Tau is released from microtubules after pathologic transformation, which renders it to interact easily with other proteins. Sequestosome-1 (SQSTM1, also known as p62) involves in tau clearance through trafficking tau into degradation machinery, which contribute to diminishing tau toxicity. The interaction between tau and p62 has been thought indirect through polyubiquitin chains which were attached to tau, however we recently identified that polyubiquitinations are not essential for interaction between two proteins. We were curious whether the binding of p62 with tau give an impact on pathogenic process of tau itself like aggregation and seeding. To elucidate it we set-up ex vitro and in vitro model using recombinant proteins and genetically modified cell lines. In response to exogenous applications of tau fibrils tau phosphorylation and aggregations were induced in tau overexpressed p62 knock-out HEK293T cell lines, but not in wildtype and p62 overexpression cells. On ex vitro assay using Thioflavin T the recombinant protein of p62 was effective in inhibiting heparin-induced K18 tau aggregations. The aggregation inhibiting effect was similar to that of methylene blue when compared at the same concentration of 0.6 μM. However, the comparable effect became different at higher concentration, 2.5 μM to show lower efficacy in p62. Next, we explored the domain-specific effect of p62 on tau aggregation. We produced another recombinant protein, p62ΔTB in which TB domain was deleted. Ex vitro aggregation test demonstrated that decreased efficiency of p62 in inhibiting K18 tau aggregations in the absence of TB domain. In conclusion, our study demonstrates that p62 prevents the pathologic conversion of tau proteins to insoluble aggregates by tau fibril seeder and heparin-induced tau aggregations. It suggests that to modulate p62 could be a possible therapeutic strategy in neurodegenerative disorders with predominant tau pathology.
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- Appears in Collections:
- Graduate School of Ajou University > Department of Biomedical Sciences > 3. Theses(Master)
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