Neuroectoderm-specific deletion of cathepsin D in mice models human inherited neuronal ceroid lipofuscinosis type 10

Ketscher, Anett; Ketterer, Stephanie; Dollwet-Mack, Susanne; Reif, Ulrike; Reinheckel, Thomas

doi:10.1016/j.biochi.2015.07.020

Cited by 22 publications

(25 citation statements)

References 19 publications

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“…Indeed, loss-of-function mutations of the CTSD gene are linked to human lysosome storage disease such as neuronal ceroid lipofuscinosis type 10 (NCL10); 26, 46 and mice with global or neuroectoderm-specific deletion of Ctsd display abnormalities that recapitulate main manifestations of human NCL10 disease. 47 This, however, does not necessarily mean that CTSD is generally required for autophagic flux. There is evidence both for and against the notion that Ctsd is required for general autophagic flux.…”

Section: Discussionmentioning

confidence: 99%

Myocardial Upregulation of Cathepsin D by Ischemic Heart Disease Promotes Autophagic Flux and Protects Against Cardiac Remodeling and Heart Failure

Yuan

et al. 2017

Circ: Heart Failure

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Background Lysosomal dysfunction is implicated in human heart failure for which ischemic heart disease is the leading cause. Altered myocardial expression of cathepsin D (CTSD), a major lysosomal protease, was observed in human heart failure but its pathophysiological significance has not been determined. Methods and Results Western blot analyses revealed an increase in the precursor but not the mature form of CTSD in myocardial samples from explanted human failing hearts with ischemic heart disease, which is recapitulated in chronic myocardial infarction produced via coronary artery ligation in Ctsd+/+ but not Ctsd+/− mice. Mice deficient of Ctsd displayed impaired myocardial autophagosome removal, reduced autophagic flux, and restrictive cardiomyopathy. After induction of myocardial infarction, weekly serial echocardiography detected earlier occurrence of left ventricle chamber dilatation, greater decreases in ejection fraction and fractional shortening, and lesser wall thickening throughout the first 4 weeks; pressure-volume relationship analyses at 4-week revealed greater decreases in systolic and diastolic functions, stroke work, stroke volume, and cardiac output; greater increases in the ventricular weight to body weight and the lung weight to body weight ratios and larger scar size were also detected in Ctsd+/− mice compared with Ctsd+/+ mice. Significant increases of myocardial autophagic flux detected at 1 and 4 weeks after induction of myocardial infarction in the Ctsd+/+ mice were diminished in the Ctsd+/− mice. Conclusions Myocardial CTSD upregulation induced by myocardial infarction protects against cardiac remodeling and malfunction, which is at least in part through promoting myocardial autophagic flux.

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Section: Discussionmentioning

confidence: 99%

Myocardial Upregulation of Cathepsin D by Ischemic Heart Disease Promotes Autophagic Flux and Protects Against Cardiac Remodeling and Heart Failure

Yuan

et al. 2017

Circ: Heart Failure

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“…Proteins that had a significant increased content included a number of lipid binding proteins and proteases that have been identified to be increased in mammalian brains during aging and neurodegenerative disesases including the proteases Cathepsin B and D, and also the lipid binding proteins, Apolipoprotein D and E, [40] , [41] , [42] . Cathepsin D knockout mice die from a neurodegenerative liposomal storage disease [43] and it has also been reported that the lipid binding protein Apo E is a substrate of the cysteine protease Cathepsin D [34] , [44] . These lysosomal proteases have also been implicated in the degradation of α-Synuclein linked to the neuropathology of Parkinson’s disease [45] .…”

Section: Discussionmentioning

confidence: 99%

Ageing-induced changes in the redox status of peripheral motor nerves imply an effect on redox signalling rather than oxidative damage

Scullion

Vasilaki

Pollock

et al. 2016

Free Radical Biology and Medicine

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Ageing is associated with loss of skeletal muscle fibres, atrophy of the remaining fibres and weakness. These changes in muscle are accompanied by disruption of motor neurons and neuromuscular junctions although the direct relationship between the nerve and muscle degeneration is not understood. Oxidative changes have been implicated in the mechanisms leading to age-related loss of muscle mass and in degeneration of the central nervous system, but little is known about age-related changes in oxidation in specific peripheral nerves that supply muscles that are affected by ageing. We have therefore examined the sciatic nerve of old mice at an age when loss of tibialis anterior muscle mass and function is apparent. Sciatic nerve from old mice did not show a gross increase in oxidative damage, but electron paramagnetic resonance (EPR) studies indicated an increase in the activity of superoxide and/or peroxynitrite in the nerves of old mice at rest that was further exacerbated by electrical stimulation of the nerve to activate muscle contractions. Proteomic analyses indicated that specific redox-sensitive proteins are increased in content in the nerves of old mice that may reflect an adaptation to regulate the increased superoxide/peroxynitrite and maintain redox homoeostasis. Analysis of redox active cysteines showed some increase in reversible oxidation in specific proteins in nerves of old mice, but this was not universally seen across all redox-active cysteines. Detailed analysis of the redox-active cysteine in one protein in the nerve of old mice that is key to redox signalling (Peroxiredoxin 6, Cys 47) showed a minor increase in reversible oxidation that would be compatible with a change in its redox signalling function. In conclusion, the data presented indicate that sciatic nerve from old mice does not show a gross increase in oxidative damage similar to that seen in the TA and other muscles that it innervates. Our results indicate an adaptation to increased oxidation with minor changes in the oxidation of key cysteines that may contribute to defective redox signalling in the nerve.

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“…So far, no effective treatment options for type 10 CLN exist; therefore, therapy is restricted to palliative care . Naturally occurring (sheep, bulldog) and genetically engineered (mouse, fruit fly, zebrafish) animal models for type 10 CLN will help to validate the potential of enzyme replacement and gene therapy . However, due to the congenital characteristic of the disease, it will be challenging to establish novel intervention strategies.…”

Section: Cathepsins D and F Deficiencies Are Associated With Two Distmentioning

confidence: 99%

Inherited diseases caused by mutations in cathepsin protease genes

et al. 2017

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Lysosomal cathepsins are proteolytic enzymes increasingly recognized as prognostic markers and potential therapeutic targets in a variety of diseases. In those conditions, the cathepsins are mostly overexpressed, thereby driving the respective pathogenic processes. Although less known, there are also diseases with a genetic deficiency of cathepsins. In fact, nowadays 6 of the 15 human proteases called ‘cathepsins’ have been linked to inherited syndromes. However, only three of these syndromes are typical lysosomal storage diseases, while the others are apparently caused by defective cleavage of specific protein substrates. Here, we will provide an introduction on lysosomal cathepsins, followed by a brief description of the clinical symptoms of the various genetic diseases. For each disease, we focus on the known mutations of which many have been only recently identified by modern genome sequencing approaches. We further discuss the effect of the respective mutation on protease structure and activity, the resulting pathogenesis, and possible therapeutic strategies.

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Neuroectoderm-specific deletion of cathepsin D in mice models human inherited neuronal ceroid lipofuscinosis type 10

Cited by 22 publications

References 19 publications

Myocardial Upregulation of Cathepsin D by Ischemic Heart Disease Promotes Autophagic Flux and Protects Against Cardiac Remodeling and Heart Failure

Myocardial Upregulation of Cathepsin D by Ischemic Heart Disease Promotes Autophagic Flux and Protects Against Cardiac Remodeling and Heart Failure

Ageing-induced changes in the redox status of peripheral motor nerves imply an effect on redox signalling rather than oxidative damage

Inherited diseases caused by mutations in cathepsin protease genes

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