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Cathepsin B Gene Knockout Improves Behavioral Deficits and Reduces Pathology in Models of Neurologic Disorders
Gregory Hook1, Thomas Reinheckel1, Junjun Ni1
1American 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.).
Abstract:
Cathepsin B (CTSB) is a powerful lysosomal protease. This review evaluated CTSB gene knockout (KO) outcomes for amelioration of brain dysfunctions in neurologic diseases and aging animal models. Deletion of the CTSB gene resulted in significant improvements in behavioral deficits, neuropathology, and/or biomarkers in traumatic brain injury, ischemia, inflammatory pain, opiate tolerance, epilepsy, aging, transgenic Alzheimer's disease (AD), and periodontitis AD models as shown in 12 studies. One study found beneficial effects for double CTSB and cathepsin S KO mice in a multiple sclerosis model. Transgenic AD models using amyloid precursor protein (APP) mimicking common sporadic AD in three studies showed that CTSB KO improved memory, neuropathology, and biomarkers; two studies used APP representing rare familial AD and found no CTSB KO effect, and two studies used highly engineered APP constructs and reported slight increases in a biomarker. In clinical studies, all reports found that CTSB enzyme was upregulated in diverse neurologic disorders, including AD in which elevated CTSB was positively correlated with cognitive dysfunction. In a wide range of neurologic animal models, CTSB was also upregulated and not downregulated. Further, human genetic mutation data provided precedence for CTSB upregulation causing disease. Thus, the consilience of data is that CTSB gene KO results in improved brain dysfunction and reduced pathology through blockade of CTSB enzyme upregulation that causes human neurologic disease phenotypes. The overall findings provide strong support for CTSB as a rational drug target and for CTSB inhibitors as therapeutic candidates for a wide range of neurologic disorders. SIGNIFICANCE STATEMENT: This review provides a comprehensive compilation of the extensive data on the effects of deleting the cathepsin B (CTSB) gene in neurological and aging mouse models of brain disorders. Mice lacking the CTSB gene display improved neurobehavioral deficits, reduced neuropathology, and amelioration of neuronal cell death and inflammatory biomarkers. The significance of the compelling CTSB evidence is that the data consilience validates CTSB as a drug target for discovery of CTSB inhibitors as potential therapeutics for treating numerous neurological diseases.
Insights
Deleting the cathepsin B (CTSB) gene improves brain function and reduces pathology in neurologic disease models. This highlights CTSB as a potential drug target for neurological disorders.
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- Cathepsin B (CTSB) is a lysosomal protease implicated in various cellular processes.
- Upregulation of CTSB is observed in several neurological disorders and aging.
- Understanding the role of CTSB in brain dysfunction is crucial for therapeutic development.
Purpose of the Study:
- To review the outcomes of cathepsin B (CTSB) gene knockout (KO) in animal models of neurologic diseases and aging.
- To evaluate the therapeutic potential of targeting CTSB for brain dysfunction.
Main Methods:
- Systematic review of studies involving CTSB gene knockout in various neurologic and aging animal models.
- Analysis of behavioral deficits, neuropathology, and biomarkers in knockout models.
- Correlation of CTSB levels with cognitive dysfunction in clinical and animal studies.
Main Results:
- CTSB gene deletion significantly improved outcomes in models of traumatic brain injury, ischemia, epilepsy, aging, and Alzheimer's disease.
- Studies showed beneficial effects of CTSB KO on memory, neuropathology, and biomarkers.
- Clinical and animal data consistently showed CTSB upregulation in neurological disorders, correlating with dysfunction.
Conclusions:
- Consilience of data indicates that CTSB gene KO ameliorates brain dysfunction and pathology by blocking CTSB enzyme upregulation.
- CTSB is validated as a rational drug target for a wide range of neurological disorders.
- CTSB inhibitors represent promising therapeutic candidates for neurological diseases.
