Review ArticleReview Article
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Cathepsin B Gene Knockout Improves Behavioral Deficits and Reduces Pathology in Models of Neurologic Disorders
Gregory Hook, Thomas Reinheckel, Junjun Ni, Zhou Wu, Mark Kindy, Christoph Peters and Vivian Hook
Eric Barker, ASSOCIATE EDITOR
Pharmacological Reviews July 2022, 74 (3) 600-629; DOI: https://doi.org/10.1124/pharmrev.121.000527
Gregory Hook
American Life Science Pharmaceuticals, La Jolla, California (G.H.); Institute of Molecular Medicine and Cell Research, Faculty of Medicine, Albert Ludwigs University, Freiburg, Germany (T.R.); German Cancer Consortium (DKTK) Partner Site Freiburg, Freiburg, Germany (T.R.); German Cancer Research Center (DKFZ), Heidelberg, Germany (T.R); Center for Biological Signaling Studies BIOSS, Albert Ludwigs University, Freiburg, Germany (T.R.); Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, China (J.N.); Department of Aging Science and Pharmacology, OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan (Z.W); Taneja College of Pharmacy, Department of Pharmaceutical Sciences, University of South Florida, Tampa, Florida (M.K.); James A Haley VAMC, Research Service, Tampa, Florida (M.K.); Institute of Molecular Medicine and Cell Research, Faculty of Biology, Albert Ludwigs University, Freiburg, Germany (C.P.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, CA (V.H.); and Department of Neuroscience and Department of Pharmacology, School of Medicine, University of California, La Jolla, CA (V.H.)
Thomas Reinheckel
American Life Science Pharmaceuticals, La Jolla, California (G.H.); Institute of Molecular Medicine and Cell Research, Faculty of Medicine, Albert Ludwigs University, Freiburg, Germany (T.R.); German Cancer Consortium (DKTK) Partner Site Freiburg, Freiburg, Germany (T.R.); German Cancer Research Center (DKFZ), Heidelberg, Germany (T.R); Center for Biological Signaling Studies BIOSS, Albert Ludwigs University, Freiburg, Germany (T.R.); Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, China (J.N.); Department of Aging Science and Pharmacology, OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan (Z.W); Taneja College of Pharmacy, Department of Pharmaceutical Sciences, University of South Florida, Tampa, Florida (M.K.); James A Haley VAMC, Research Service, Tampa, Florida (M.K.); Institute of Molecular Medicine and Cell Research, Faculty of Biology, Albert Ludwigs University, Freiburg, Germany (C.P.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, CA (V.H.); and Department of Neuroscience and Department of Pharmacology, School of Medicine, University of California, La Jolla, CA (V.H.)
Junjun Ni
American Life Science Pharmaceuticals, La Jolla, California (G.H.); Institute of Molecular Medicine and Cell Research, Faculty of Medicine, Albert Ludwigs University, Freiburg, Germany (T.R.); German Cancer Consortium (DKTK) Partner Site Freiburg, Freiburg, Germany (T.R.); German Cancer Research Center (DKFZ), Heidelberg, Germany (T.R); Center for Biological Signaling Studies BIOSS, Albert Ludwigs University, Freiburg, Germany (T.R.); Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, China (J.N.); Department of Aging Science and Pharmacology, OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan (Z.W); Taneja College of Pharmacy, Department of Pharmaceutical Sciences, University of South Florida, Tampa, Florida (M.K.); James A Haley VAMC, Research Service, Tampa, Florida (M.K.); Institute of Molecular Medicine and Cell Research, Faculty of Biology, Albert Ludwigs University, Freiburg, Germany (C.P.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, CA (V.H.); and Department of Neuroscience and Department of Pharmacology, School of Medicine, University of California, La Jolla, CA (V.H.)
Zhou Wu
American Life Science Pharmaceuticals, La Jolla, California (G.H.); Institute of Molecular Medicine and Cell Research, Faculty of Medicine, Albert Ludwigs University, Freiburg, Germany (T.R.); German Cancer Consortium (DKTK) Partner Site Freiburg, Freiburg, Germany (T.R.); German Cancer Research Center (DKFZ), Heidelberg, Germany (T.R); Center for Biological Signaling Studies BIOSS, Albert Ludwigs University, Freiburg, Germany (T.R.); Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, China (J.N.); Department of Aging Science and Pharmacology, OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan (Z.W); Taneja College of Pharmacy, Department of Pharmaceutical Sciences, University of South Florida, Tampa, Florida (M.K.); James A Haley VAMC, Research Service, Tampa, Florida (M.K.); Institute of Molecular Medicine and Cell Research, Faculty of Biology, Albert Ludwigs University, Freiburg, Germany (C.P.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, CA (V.H.); and Department of Neuroscience and Department of Pharmacology, School of Medicine, University of California, La Jolla, CA (V.H.)
Mark Kindy
American Life Science Pharmaceuticals, La Jolla, California (G.H.); Institute of Molecular Medicine and Cell Research, Faculty of Medicine, Albert Ludwigs University, Freiburg, Germany (T.R.); German Cancer Consortium (DKTK) Partner Site Freiburg, Freiburg, Germany (T.R.); German Cancer Research Center (DKFZ), Heidelberg, Germany (T.R); Center for Biological Signaling Studies BIOSS, Albert Ludwigs University, Freiburg, Germany (T.R.); Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, China (J.N.); Department of Aging Science and Pharmacology, OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan (Z.W); Taneja College of Pharmacy, Department of Pharmaceutical Sciences, University of South Florida, Tampa, Florida (M.K.); James A Haley VAMC, Research Service, Tampa, Florida (M.K.); Institute of Molecular Medicine and Cell Research, Faculty of Biology, Albert Ludwigs University, Freiburg, Germany (C.P.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, CA (V.H.); and Department of Neuroscience and Department of Pharmacology, School of Medicine, University of California, La Jolla, CA (V.H.)
Christoph Peters
American Life Science Pharmaceuticals, La Jolla, California (G.H.); Institute of Molecular Medicine and Cell Research, Faculty of Medicine, Albert Ludwigs University, Freiburg, Germany (T.R.); German Cancer Consortium (DKTK) Partner Site Freiburg, Freiburg, Germany (T.R.); German Cancer Research Center (DKFZ), Heidelberg, Germany (T.R); Center for Biological Signaling Studies BIOSS, Albert Ludwigs University, Freiburg, Germany (T.R.); Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, China (J.N.); Department of Aging Science and Pharmacology, OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan (Z.W); Taneja College of Pharmacy, Department of Pharmaceutical Sciences, University of South Florida, Tampa, Florida (M.K.); James A Haley VAMC, Research Service, Tampa, Florida (M.K.); Institute of Molecular Medicine and Cell Research, Faculty of Biology, Albert Ludwigs University, Freiburg, Germany (C.P.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, CA (V.H.); and Department of Neuroscience and Department of Pharmacology, School of Medicine, University of California, La Jolla, CA (V.H.)
Vivian Hook
American Life Science Pharmaceuticals, La Jolla, California (G.H.); Institute of Molecular Medicine and Cell Research, Faculty of Medicine, Albert Ludwigs University, Freiburg, Germany (T.R.); German Cancer Consortium (DKTK) Partner Site Freiburg, Freiburg, Germany (T.R.); German Cancer Research Center (DKFZ), Heidelberg, Germany (T.R); Center for Biological Signaling Studies BIOSS, Albert Ludwigs University, Freiburg, Germany (T.R.); Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, China (J.N.); Department of Aging Science and Pharmacology, OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan (Z.W); Taneja College of Pharmacy, Department of Pharmaceutical Sciences, University of South Florida, Tampa, Florida (M.K.); James A Haley VAMC, Research Service, Tampa, Florida (M.K.); Institute of Molecular Medicine and Cell Research, Faculty of Biology, Albert Ludwigs University, Freiburg, Germany (C.P.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, CA (V.H.); and Department of Neuroscience and Department of Pharmacology, School of Medicine, University of California, La Jolla, CA (V.H.)
Eric Barker
Roles: ASSOCIATE EDITOR

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Review ArticleReview Article
Cathepsin B in Neurologic Diseases
Gregory Hook, Thomas Reinheckel, Junjun Ni, Zhou Wu, Mark Kindy, Christoph Peters and Vivian Hook
Pharmacological Reviews July 1, 2022, 74 (3) 600-629; DOI: https://doi.org/10.1124/pharmrev.121.000527
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- Article
- Abstract
- I. Introduction
- II. Cathepsin B is Elevated in Human Neurologic Disorders
- III. Cathepsin B Genetic Mutations Increase Cathepsin B and Cause Human Diseases
- IV. Cathepsin B Is Elevated in Animal Models of Neurologic Diseases
- V. Cathepsin B Neurobiology
- VI. Gene Knockout Mice for Target Validation and Drug Discovery
- VII. Cathepsin B Knockout Mice Are Generally Indistinguishable from Wild-Type Healthy Animals
- VIII. Cathepsin B Knockout Improves Behavioral Deficits in Neurologic Disease Animal Models
- IX. Cathepsin B Upregulation Is a Common Response in Neurologic Disorders and Causes Cellular Pathology by Multiple Specific Mechanisms
- X. Summary and Conclusion: Cathepsin B Knockout Data Validates Cathepsin B as a Drug Target for Development of Cathepsin B Inhibitors as Potentially New Therapeutics for Neurologic Disorders
- XI. Significance
- Acknowledgments
- Authorship Contributions
- Footnotes
- Abbreviations
- References
- Figures & Data
- Info & Metrics
- eLetters
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