Cathepsin B Gene Knockout Improves Behavioral Deficits and Reduces Pathology in Models of Neurologic Disorders

Hook, Gary E. R.; Reinheckel, Thomas; Ni, Junjun; Wu, Zhou; Kindy, Mark S.; Peters, Christoph; Hook, Vivian

doi:10.1124/pharmrev.121.000527

Cited by 42 publications

(51 citation statements)

References 286 publications

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“…As CTSB and CTSD are both involved in the processing and regulation of each other, [16,20–28] simultaneous monitoring of CTSB and CTSD activities is essential for validating the activity of cathepsins and for investigating the relationship of each other in the proteolytic network. For this purpose, CtBsub‐ODN1 and CtDsub‐ODN2 in the same concentrations were mixed to test the simultaneous detection of CTSB and CTSD.…”

Section: Resultsmentioning

confidence: 99%

“…The conjugated ODN likely improved the solubility of cathepsin probes modified with the hydrophobic and bulky dyes, especially in the case of CtBsub. CtBsub‐ODN1 and CtDsub‐ODN2 simultaneously detected the activity of CTSB and CTSD, providing potent tools to monitor the synchronous activities of CTSB and CTSD in the cell because both CTSB and CTSD were reported to take part in the regulation to one another [16,20–28] . Conjugation with ODN is a convenient way not only to mitigate the often hydrophobic nature of FRET‐based probes to detect the activity of protease, [37] but also to provide a handle to specifically assemble FRET‐based probes through hybridization with the complementary DNA strand.…”

Section: Discussionmentioning

confidence: 99%

“…From the reciprocal plot of the substrate concentrations against the initial velocity, k cat /K m of CtBsub-ODN1 with CTSB was estimated as (2.6 � 0.1) × 10 3 M À 1 s À 1 , and CtDsub-ODN2 with CTSD was (1.7 � 0.1) × 10 5 M À 1 s À 1 , respectively (Figure S8 in the Supporting Information). [34,36] As CTSB and CTSD are both involved in the processing and regulation of each other, [16,[20][21][22][23][24][25][26][27][28] simultaneous monitoring of CTSB and CTSD activities is essential for validating the activity of cathepsins and for investigating the relationship of each other in the proteolytic network. For this purpose, CtBsub-ODN1 and CtDsub-ODN2 in the same concentrations were mixed to test the simultaneous detection of CTSB and CTSD.…”

Section: Chembiochemmentioning

confidence: 99%

“…However, there is a need for monitoring the physiological information associated with the action of CTSB, such as the local pH, concentrations of metabolites, and activities of other enzymes related to CTSB, simultaneously by other probes to further understand the interplay of CTSB in proteolytic processes revised [16–19] . For example, cathepsin D (CTSD), an aspartic protease universally found inside lysosomes, is an important protease and shows a complex relationship with CTSB [20–25] . CTSD is processed to be matured in cells by subsequent proteolytic cleavage involving CTSB and other cysteine proteases [26,27] .…”

Section: Introductionmentioning

confidence: 99%

“…[16][17][18][19] For example, cathepsin D (CTSD), an aspartic protease universally found inside lysosomes, is an important protease and shows a complex relationship with CTSB. [20][21][22][23][24][25] CTSD is processed to be matured in cells by subsequent proteolytic cleavage involving CTSB and other cysteine proteases. [26,27] It is also reported that CTSB is activated by CTSD (Figure S1 in the Supporting Information).…”

Section: Introductionmentioning

confidence: 99%

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FRET‐Based Cathepsin Probes for Simultaneous Detection of Cathepsin B and D Activities

et al. 2022

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Fluorescent cathepsin probes were prepared by modification of peptidic substrates for cathepsin B (CTSB) and cathepsin D (CTSD) with FRET pairs. Fluorophores with distinguishable emission characteristics were applied to CTSB and CTSD probes with their appropriate quenchers to simultaneously monitor the activity of CTSB and/or CTSD. Conjugation of both the CTSB and CTSD probes with short single-stranded DNA drastically increased their reactivity to cathepsins over the parent probes possibly by improving their solubility. The activity of CTSB and CTSD were simultaneously detected by using these orthogonal FRET-based cathepsin probes.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Chembiochemmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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FRET‐Based Cathepsin Probes for Simultaneous Detection of Cathepsin B and D Activities

et al. 2022

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Endo‐lysosomal protein concentrations in CSF from patients with frontotemporal dementia caused by CHMP2B mutation

Toft

Sjödin

Simonsen

et al. 2023

Alz & Dem Diag Ass & Dis Mo

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Introduction: Increasing evidence implicates proteostatic dysfunction as an early event in the development of frontotemporal dementia (FTD). This study aimed to explore potential cerebrospinal fluid (CSF) biomarkers associated with the proteolytic systems in genetic FTD caused by CHMP2B mutation. Methods: Combining solid-phase extraction and parallel reaction monitoring mass spectrometry, a panel of 47 peptides derived from 20 proteins was analyzed in CSF from 31 members of the Danish CHMP2B-FTD family.Results: Compared with family controls, mutation carriers had significantly higher levels of complement C9, lysozyme and transcobalamin II, and lower levels of ubiquitin, cathepsin B, and amyloid precursor protein.Discussion: Lower CSF ubiquitin concentrations in CHMP2B mutation carriers indicate that ubiquitin levels relate to the specific disease pathology, rather than all-cause neurodegeneration. Increased lysozyme and complement proteins may indicate innate immune activation. Altered levels of amyloid precursor protein and cathepsins have previously been associated with impaired lysosomal proteolysis in FTD.

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An atlas of caspase cleavage events in differentiating muscle cells

Gomez‐Cardona,

Dehkordi,

Van Baar

et al. 2024

Protein Science

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Executioner caspases, such as caspase‐3, are known to induce apoptosis, but in other contexts, they can control very different fates, including cell differentiation and neuronal plasticity. While hundreds of caspase substrates are known to be specifically targeted during cell death, we know very little about how caspase activity brings about non‐apoptotic fates. Here, we report the first proteome identification of cleavage events in C2C12 cells undergoing myogenic differentiation and its comparison to undifferentiated or dying C2C12 cells. These data have identified new caspase substrates, including caspase substrates specifically associated with differentiation, and show that caspases are regulating proteins involved in myogenesis in myotubes, several days after caspase‐3 initiated differentiation. Cytoskeletal proteins emerged as a major group of non‐apoptotic caspase substrates. We also identified proteins with well‐established roles in muscle differentiation as substrates cleaved in differentiating cells.

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Cathepsin B Gene Knockout Improves Behavioral Deficits and Reduces Pathology in Models of Neurologic Disorders

Cited by 42 publications

References 286 publications

FRET‐Based Cathepsin Probes for Simultaneous Detection of Cathepsin B and D Activities

FRET‐Based Cathepsin Probes for Simultaneous Detection of Cathepsin B and D Activities

Endo‐lysosomal protein concentrations in CSF from patients with frontotemporal dementia caused by CHMP2B mutation

An atlas of caspase cleavage events in differentiating muscle cells

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