Enzyme lysosomal cathepsin D bảo vệ chống lại sự tích tụ và độc tính của alpha-synuclein

Molecular Brain - Tập 1 Số 1 - 2008
Li Qiao1, Shusei Hamamichi2, Kim A. Caldwell2, Talene A. Yacoubian3, Scott Wilson4, Zuolei Xie1, Lisa D Speake1, Rachael Parks1, Donna Crabtree1, Qiwei Liang1, Stephen Crimmins1, Lonnie Schneider1, Yasuo Uchiyama5, Takeshi Iwatsubo6, Yi Zhou4, Lisheng Peng7, Youming Lu7, David Standaert3, Ken C. Walls1, John J. Shacka8,9, Kevin A. Roth8, Jianhua Zhang8
1Department of Pathology, University of Alabama at Birmingham, Birmingham, USA </br>
2Department of Biological Sciences, The University of Alabama, Tuscaloosa, USA
3Department of Neurology, University of Alabama at Birmingham, Birmingham, USA
4Department of Neurobiology, University of Alabama at Birmingham, Birmingham, USA
5Department of Cell Biology and Neurosciences, Osaka University, Osaka, Japan
6Department of Neuropathology, Department of Neuropathology and Neuroscience, Graduate School of Medicine, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
7Biomolecular Science Center, Burnett College of Biomedical Sciences, Orlando, USA
8Department of Pathology, University of Alabama at Birmingham, Birmingham, USA
9Department of Veterans Affairs, Birmingham VA Medical Center, Birmingham, USA

Tóm tắt

Tóm tắtα-synuclein (α-syn) là thành phần chính của các thể Lewy (LB) mà xảy ra trong nhiều bệnh thoái hóa thần kinh, bao gồm bệnh Parkinson (PD), sa sút trí tuệ có thể Lewy (DLB) và suy giảm đa hệ thống. Các đột biến hoặc gia tăng α-syn chịu trách nhiệm cho một tập hợp các trường hợp PD gia đình chi phối tự động với tính ưu thế, và sự biểu hiện quá mức gây ra thoái hóa thần kinh và rối loạn vận động ở động vật. Để điều tra cơ chế tích tụ và độc tính của α-syn, chúng tôi đã nghiên cứu mô hình chuột có sự thiếu hụt enzyme lysosomal cathepsin D (CD), và phát hiện sự tích tụ rộng rãi của α-syn nội sinh trong các tế bào thần kinh mà không có sự gia tăng hàm lượng mRNA của α-syn. Ngoài việc suy giảm tự thực bào lớn, sự thiếu hụt CD đã làm giảm hoạt động của proteasome, cho thấy vai trò thiết yếu của chức năng CD lysosomal trong việc điều chỉnh nhiều con đường phân giải protein quan trọng cho sự trao đổi chất của α-syn. Ngược lại, sự biểu hiện quá mức của CD làm giảm sự tích tụ α-syn và bảo vệ thần kinh chống lại cái chết tế bào do sự biểu hiện quá mức α-syn gây ra trong ống nghiệm. Trong mô hình C. elegans, sự thiếu hụt CD làm trầm trọng thêm sự tích tụ α-syn trong khi sự biểu hiện quá mức của CD bảo vệ chống lại thoái hóa thần kinh dopaminergic do α-syn gây ra. CD đột biến với hoạt động enzyme giảm hoặc sự biểu hiện quá mức của các cathepsin B (CB) hoặc L (CL) không có tác dụng bảo vệ trong mô hình giun, cho thấy yêu cầu độc đáo cho CD hoạt động enzyme. Dữ liệu của chúng tôi xác định một chức năng CD bảo tồn trong sự phân hủy α-syn và xác định CD như một mục tiêu mới cho liệu pháp bệnh LB.

Từ khóa


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