Sự ức chế HDAC6 khôi phục các khiếm khuyết vận chuyển trục trong các nơron vận động từ bệnh nhân FUS-ALS

Nature Communications - Tập 8 Số 1
Wenting Guo1, Maximilian Naujock2, Laura Fumagalli1, Tijs Vandoorne1, Pieter Baatsen3, Ruben Boon4, Laura Ordovás4, Abdulsamie Patel4, Marc Welters4, Thomas Vanwelden4, Natasja Geens5, Tine Tricot4, Veronick Benoy5, Jolien Steyaert5, Cynthia Lefebvre-Omar6, Werend Boesmans7, Matthew Jarpe8, Jared Sterneckert9, Florian Wegner2, Susanne Petri2, Delphine Bohl6, Pieter Vanden Berghe7, Pamela J. Shaw10, Philip Van Damme5, Cathérine Verfaillie4, Ludo Van Den Bosch5
1KU Leuven-Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND), Leuven, 3000, Belgium
2Department of Neurology, Hannover Medical School, Hannover 30625, Germany
3VIB Bio Imaging Core and VIB-KU Leuven, Center for Brain and Disease Research, Leuven, 3000, Belgium
4KU Leuven-Stem Cell Institute (SCIL), Leuven, 3000, Belgium
5VIB, Center for Brain and Disease Research, Laboratory of Neurobiology, Leuven, 3000, Belgium
6Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 6, Institut du Cerveau et de la Moelle épinière (ICM), Hôpital Pitié-Salpêtrière, Paris, 75013, France
7Lab for Enteric NeuroScience, TARGID, KU Leuven, Leuven, 3000, Belgium
8Acetylon Pharmaceuticals Inc., Boston, MA 02210, USA
9Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, 01069, Germany
10University Hospitals Leuven, Department of Neurology, Leuven, 3000, Belgium

Tóm tắt

Tóm tắt

Bệnh xơ cứng teo cơ một bên (ALS) là một rối loạn thoái hóa thần kinh tiến triển nhanh chóng do mất chọn lọc các nơron vận động (MNs). Các đột biến trong gen hòa nhập sarcoma (FUS) có thể gây ra cả ALS khởi phát ở tuổi thiếu niên và khởi phát muộn. Chúng tôi đã tạo ra và xác định các tế bào gốc đa năng cảm ứng (iPSCs) từ bệnh nhân ALS có các đột biến FUS khác nhau, cũng như từ các đối chứng khỏe mạnh. Các nơron vận động lấy từ bệnh nhân thể hiện đặc điểm bệnh lý FUS điển hình trong bào tương, giảm tính hưng phấn, cũng như các khiếm khuyết trong vận chuyển trục diễn tiến. Các khiếm khuyết trong vận chuyển trục được cứu chữa thông qua việc chỉnh sửa di truyền bằng CRISPR/Cas9 đối với đột biến FUS trong các iPSCs lấy từ bệnh nhân. Hơn nữa, những khiếm khuyết này được tái tạo bằng cách biểu hiện FUS đột biến trong các tế bào gốc phôi người (hESCs), trong khi việc giảm biểu hiện FUS nội sinh không có tác động, xác nhận rằng những thay đổi bệnh lý này phụ thuộc vào FUS đột biến. Sự ức chế dược lý cũng như sự làm im lặng di truyền của histone deacetylase 6 (HDAC6) làm tăng acetyl hóa α-tubulin, sự chồng chéo giữa mạng lưới nội chất (ER) và ty thể, và khôi phục các khiếm khuyết trong vận chuyển trục ở các nơron vận động lấy từ bệnh nhân.

Từ khóa

#ALS #tế bào gốc đa năng cảm ứng #đột biến FUS #nơron vận động #HDAC6

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