Nghiên cứu ảnh hưởng của đột biến lên cấu trúc và động học của chuỗi peptide amyloid beta hướng đến ức chế bệnh alzheimer

ĐẠI HỌC QUỐC GIA TP HCM TRƯỜNG ĐẠI HỌC BÁCH KHOA TRẦN THỊ MINH THƯ NGHIÊN CỨU ẢNH HƯỞNG CỦA ĐỘT BIẾN LÊN CẤU TRÚC VÀ ĐỘNG HỌC CỦA CHUỖI PEPTID AMYLOID BETA: HƯỚNG ĐẾN ỨC CHẾ BỆNH ALZHEIMER LUẬN ÁN TIẾN SĨ TP HỒ CHÍ MINH - NĂM 2020 ĐẠI HỌC QUỐC GIA TP HCM TRƯỜNG ĐẠI HỌC BÁCH KHOA NGHIÊN CỨU ẢNH HƯỞNG CỦA ĐỘT BIẾN LÊN CẤU TRÚC VÀ ĐỘNG HỌC CỦA CHUỖI PEPTID AMYLOID BETA: HƯỚNG ĐẾN ỨC CHẾ BỆNH ALZHEIMER Chuyên ngành: Vật lý kỹ thuật Mã số chuyên ngành: 62520401 Phản biện độc lập 1: PGS TS Lê Thị Lý Phản biện độc lập 2: TS Nguyễn Trung Hải Phản biện 1: GS TS Nguyễn Quốc Khánh Phản biện 2: PGS TS Thái Khắc Minh Phản biện 3: PGS TS Huỳnh Quang Linh NGƯỜI HƯỚNG DẪN: GS TSKH Mai Xuân Lý TS Lý Anh Tú LỜI CAM ĐOAN Tôi xin cam đoan cơng trình nghiên cứu khoa học độc lập hướng dẫn GS.TSKH Mai Xuân Lý, TS Lý Anh Tú nhóm thực Các kết nghiên cứu kết luận luận án trung thực, không chép từ nguồn hình thức Việc tham khảo nguồn tài liệu thực trích dẫn ghi nguồn tài liệu tham khảo quy định Tác giả luận án Trần Thị Minh Thư i TÓM TẮT LUẬN ÁN Bệnh Alzheimer (AD) chứng suy giảm não nguyên nhân gây sa sút trí tuệ người AD cho có liên quan đến việc suy giảm neuron khớp nối thần kinh não Kể từ thời điểm phát AD đến nay, nguyên nhân gây bệnh chưa xác định cách cụ thể Tuy vậy, có ba giả thuyết thể ngun nhân giả thuyết cholinergic, giả thuyết protein tau giả thuyết amyloid Trong đó, giả thuyết amyloid nghiên cứu rộng rãi với lượng thông tin liệu lớn so với hai giả thuyết lại Giả thuyết amyloid nhấn mạnh tăng sinh peptid amyloid beta (Aβ) dẫn tới tích tụ ngoại bào Aβ não theo thời gian, kết hình thành nên mảng amyloid gây viêm, kéo theo tổn thương khớp nối thần kinh làm giảm số lượng neuron Peptid Aβ cắt từ protein tiền tố (amyloid precursor protein - APP) enzyme chức β, γ-secretases có độ dài chuỗi thay đổi khoảng 36-43 acid amin Hai dạng phổ biến peptid Aβ Aβ40 (gồm 40 acid amin) Aβ42 (gồm 42 acid amin) Chuỗi peptid Aβ42 khác Aβ40 hai acid amin cuối Ile41 Ala42 có tính chất khác biệt so với Aβ40 Peptid Aβ42 tạo sợi nhanh hơn, độc thành phần yếu cấu thành mảng bám amyloid, có số lượng Aβ40 Để làm rõ ảnh hưởng hai acid amin cuối cùng, nghiên cứu sinh (NCS) tiến hành nghiên cứu mô thực nghiệm ống nghiệm cho chuỗi Aβ40, Aβ41 Aβ42 Kết cho thấy Ala42 ảnh hưởng lên việc gia tăng vận tốc tạo sợi độc tố Aβ42 Ile41 Một cách ức chế bệnh Alzheimer làm giảm vận tốc tạo sợi peptid Aβ thông qua việc gây đột biến chuỗi Đã có nhiều nghiên cứu đột biến chuỗi peptid Aβ nhằm hướng đến ức chế bênh Alzheimer Nghiên cứu thực nghiệm cho thấy, đột biến ba điểm G33V-V36P-G38V (VPV) đẩy mạnh trình tạo sợi Aβ42 làm đột biến Aβ40-VPV có hành xử cuộn giống Aβ42 thể tự nhiên, đồng thời làm tăng độc tố Bằng mô cấu trúc Aβ thể tự nhiên đột biến đoạn ngắn 31-40, 31-42 ii chuỗi đầy đủ độ dài, NCS đưa đến kết luận tương đồng động học tích tụ Aβ40-VPV Aβ42-WT gây nên gia tăng cấu trúc β tồn chuỗi có đột biến Sự thay đổi Aβ42 chịu tác động đột biến VPV dựa gia tăng cấu trúc β-turn β-hairpin acid amin 36-37 đầu C chuỗi Cấu trúc khóa kéo motif glycin đầu C cho ảnh hưởng đáng kể đến vận tốc tạo sợi hình thành độc tố peptid Aβ Để khảo sát ảnh hưởng cấu trúc motif glycin lên tính chất Aβ42, chúng tơi nghiên cứu đột biến G37V thông qua thực nghiệm ống nghiệm mơ tính tốn động lực học phân tử cổ điển Kết cho thấy đột biến G37V làm giảm mạnh độc tố Aβ42 không thay đổi vận tốc tạo sợi thành phần cấu trúc bậc hai Các phân tích thực nghiệm cho thấy hình thái tích tụ đột biến G37V tạo thành mảng có hình dạng ellipse sợi lưới Aβ42 thể tự nhiên Sự khác biệt hình thái tích tụ nguyên nhân dẫn tới suy giảm độc tố Kết mô cho thấy G37V làm tăng thành phần β-turn β-hairpin acid amin 36-37 có phân bố khoảng cách cầu muối (SB) Asp23-Lys28 linh hoạt so với thể tự nhiên Những đặc tính cấu trúc nguyên nhân dẫn đến thay đổi hình thái sợi Aβ chuyển từ dạng lưới sang dạng ellipse Các nghiên cứu trước cho ảnh hưởng môi trường (nồng độ pH, nồng độ muối, nhiệt độ…) từ cấu trúc nội (độ kị nước, điện tích, xu hướng tạo sợi trạng thái monomer, độ bền học…) yếu tố kiểm soát vận tốc tạo sợi protein Cấu trúc tìm từ thực nghiệm cho thấy trạng thái sợi protein bao gồm phiến β chéo Do đó, chúng tơi đưa giả thuyết monomer có thành phần nhiều β cho tạo sợi nhanh monomer có thành phần β nghiên cứu cấu trúc monomner giúp suy luận trình hình thành sợi Tuy nhiên yếu tố quan trọng chưa minh chứng cách rõ ràng Trong luận án này, NCS sử dụng vận tốc tạo sợi κ xác định từ công bố thực nghiệm trước tiến hành mô cho Aβ42 thể tự nhiên 19 đột biến để tính tốn thành phần cấu trúc β thạng thái monomer Hệ số tương quan cao mối quan hệ vật tốc tạo sợi iii thực nghiệm thành phần β cho phép khẳng định cấu trúc β trạng thái monomer kiểm soát tốc độ tạo sợi Aβ42 Hàm phụ thuộc vận tốc tạo sợi vào thành phần β thể dạng tuyến tính hàm mũ exp Nếu tỉ lệ phần trăm β lớn, vận tốc tạo sợi nhanh Các kết mô trả lời câu hỏi quan trọng phụ thuộc vận tốc tạo sợi vào thành phần β cách định lượng Công thức liên hệ vận tốc tạo sợi thành phần β cho phép xác định tốc độ tạo sợi protein thực nghiệm dựa thành phần β cấu trúc monomer, giá trị tính mơ máy tính iv ABSTRACT Alzheimer's disease (AD) is a brain-damaged disease and the main cause of dementia in humans AD is thought to be involved in the weakening of neurons and synapses in the brain Since AD was discovered, the cause of AD has not been identified, but there are three main hypotheses about it: cholinergic, protein tau, and amyloid Genetic and pathological data accumulated over the last decades have convincingly confirmed the third amyloid hypothesis, according to which extracellular accumulation of beta-amyloid (Aβ) peptides in the brain leads to the formation of inflammatory amyloid plaques This can damage synapses, entangle nerve fibers, and kill neurons Aβ peptides, cleaved from amyloid precursor protein (APP) by β- and γ-secretases, have 36-43 residues but Aβ40 (40 amino acids) and Aβ42 (42 amino acids) are most abundant Aβ40 and Aβ42 have identical sequences, with the exception of the last two hydrophobic residues Ile41 and Ala42, which strongly distinguish their behavior Aβ42 aggregates faster, is more toxic and is the major constituent of amyloid plaques, despite being present in lower abundance than Aβ40 To shed light on the role of the last two residues, we performed in silico and in vitro experiments for Aβ40, Aβ41 and Aβ42 We found that Ala42 has a stronger effect than Ile41on the increased fibril formation rate and consequently neurotoxicity of Aβ peptides One of the possible strategies for treating AD is to slow down Aβ aggregation by mutations in Aβ peptides, which has prompted many studies in this area It has been shown experimentally that the triple mutation G33V-V36P-G38V (VPV) significantly accelerates the self-assembly of Aβ42 and makes the mutant Aβ40-VPV behave like wildtype Aβ42 (Aβ42-WT) with increased toxicity Conducting MD simulations of fragments Aβ31-40 and Aβ31-42, and full length Aβ1-40 and Aβ1-42, we found that the similarity in folding pathways of Aβ40-VPV and Aβ42-WT was caused by the increase of β-content in the whole sequence The structural changes of Aβ42 under VPV mutation was due to the enhancement on β-hairpin and β-turn at amino acids 36-37 at the C-terminal Conducting MD simulations of the Aβ31-40 and Aβ31-42 fragments, as well as full-length Aβ1-40 v and Aβ1-42, we found that the similarity of the folding pathways of Aβ40-VPV and Aβ42-WT was caused by an increase in β-content in the entire sequence Structural changes in Aβ42 with VPV mutation were associated with an increase of population of the β-hairpin and β-turn centered at amino acids 36-37 of the C-terminus The glycine zipper motif at the C-terminus markedly influences the aggregation rate and toxicity of the Aβ peptide To demonstrate this, we studied the G37V mutation where glycine was with valine at position 37 using both MD modeling and in vitro experiment The G37V mutation was found to significantly reduce toxicity but leave the aggregation rate and secondary structures nearly unchanged For the first time we observed that the mutation alters the morphology of the aggregate such that the fibril has a network-like shape in the Aβ42-WT case, while the elliptical structure occurs upon G37V mutation Thus, our result suggests that changes in toxicity are associated with changes in the aggregate morphology MD simulations revealed that the G37V mutation enhances the βturn and β-hairpin content at the C-terminus and makes the Asp23-Lys28 salt bridge more flexible These structural changes may be responsible for the appearance of the ellipse-like morphology Previous studies have shown that environmental factors (pH, temperature, salt concentration, etc.) and intrinsic properties of population of fibril-prone conformation a protein (hydrophobicity, charge, in monomeric state, mechanical stability of fibrils) control the rate of protein aggregation Since the structure of fibrils consists of cross β-sheets, and the monomer can serve as a template for aggregation, the β content in the monomeric state seems to promote the fibril formation Thus, we hypothesize that the higher the β content in the monomeric state, the faster the fibril is formed To confirm this hypothesis, we calculated the β-content of the wild-type and 19 mutations of Aβ42 using all-atom replica exchange molecular dynamics (REMD) simulations in implicit water We found that the experimentally measured aggregation rate of these variants increases exponentially with increasing β-content Since the correlation between our computational result and experimental data is high, we conclude that the β-content in the monomeric vi state controls the rate of protein aggregation Currently, the calculation of the fibril formation time of proteins using all-atom simulations is prohibited due to the large gap between the real time (days) and the computation time (ms) From this point of view, our result is very useful, as it opens up a new way to estimate the rate of fibril formation using β-content, which can be easily obtained using REMD simulations vii LỜI CÁM ƠN Người tơi muốn bày tỏ lịng biết ơn GS TSKH Mai Xuân Lý (Mai Suan Li) May mắn gặp Thầy Thầy nhận hướng dẫn Nghiên cứu sinh bước ngoặt lớn nghiệp Thầy người truyền kiến thức, nguồn cảm hứng khơi gợi đam mê nghiên cứu khoa học Ngồi tơi học từ Thầy cách làm khoa học cách nghiêm túc chuyên nghiệp, giữ gìn đạo đức nghề nghiệp để góc nhìn khoa học thực sáng công tâm Nhờ học trị Thầy mà tơi tạo điều kiện để tham gia Hội nghị khoa học Quốc tế, có dịp gặp gỡ nhà khoa học hàng đầu lĩnh vực, để từ mở mang kiến thức giúp phát triển lâu bền nghiệp nghiên cứu thân Tôi xin cám ơn TS Lý Anh Tú, đóng góp to lớn Thầy q trình tơi thực luận án Thầy hướng dẫn cách làm khoa học đắn hiệu Những ý kiến chỉnh sửa Thầy sau lần báo cáo chuyên đề, seminar giúp tơi hồn thiện kiến thức phương pháp nghiên cứu Sự nhiệt tình tận tâm Thầy nguồn động viên lớn lao trình học tập nghiên cứu Tơi xin cám ơn Thầy Cô thuộc Khoa Khoa học ứng dụng đặc biệt PGS TS Huỳnh Quang Linh nhiệt tình giúp đỡ thủ tục góp ý sâu sắc chuyên môn Xin cám ơn Thầy Cơ cơng tác phịng Sau Đại học trường đại học Bách khoa TPHCM hỗ trợ để hồn thành đề tài nghiên cứu Tơi xin chân thành cám ơn đồng nghiệp Phòng Thí nghiệm Khoa học sống, Viện Khoa học cơng nghệ tính tốn TPHCM Bộ mơn Vật liệu nano Màng mỏng, Khoa Khoa học Công nghệ Vật liệu, Trường Đại học Khoa học Tự nhiên TPHCM tạo điều kiện, hỗ trợ suốt trình thực đề tài Tôi xin bày tỏ lịng biết ơn đến người bạn thuộc phịng thí nghiệm Khoa học tính tốn, trường đại học Bách khoa chia sẻ kiến thức khó khăn suốt q trình học tập Tơi xin bày tỏ lịng biết ơn sâu sắc đến gia đình hy sinh bền bỉ, kiên nhẫn lòng vị tha suốt thời gian thực luận án Sau cùng, xin cám ơn người bạn đời hai gái tiếp thêm động lực lúc tơi thấy khó khăn viii [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] of the blood-brain barrier in Alzheimers disease," in 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