Similarities and differences in the biogenesis, processing and lysosomal targeting between zebrafish and human pro-Cathepsin D: Functional implications

Follo, Carlo; Ozzano, Matteo; Montalenti, Claudia; Ekkapongpisit, Maneerat; Isidoro, Ciro

doi:10.1016/j.biocel.2012.10.010

Cited by 6 publications

(5 citation statements)

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“… 8 Intriguingly, the genetic ablation of cathepsin D in zebrafish reflected in dystrophic development of the skeletal musculature. 42 Here we show that p53 null myoblasts imperfectly develop into myotubes. We speculate that it is the clearance of damaged mitochondria (mitophagy) that is specifically affected in the absence of p53 as shown by accumulation of abnormal mitochondria in p53 null myotubes ( Supplementary Figure 3S ).…”

Section: Discussionmentioning

confidence: 64%

The fine tuning of metabolism, autophagy and differentiation during in vitro myogenesis

et al. 2016

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Although the mechanisms controlling skeletal muscle homeostasis have been identified, there is a lack of knowledge of the integrated dynamic processes occurring during myogenesis and their regulation. Here, metabolism, autophagy and differentiation were concomitantly analyzed in mouse muscle satellite cell (MSC)-derived myoblasts and their cross-talk addressed by drug and genetic manipulation. We show that increased mitochondrial biogenesis and activation of mammalian target of rapamycin complex 1 inactivation-independent basal autophagy characterize the conversion of myoblasts into myotubes. Notably, inhibition of autophagic flux halts cell fusion in the latest stages of differentiation and, conversely, when the fusion step of myocytes is impaired the biogenesis of autophagosomes is also impaired. By using myoblasts derived from p53 null mice, we show that in the absence of p53 glycolysis prevails and mitochondrial biogenesis is strongly impaired. P53 null myoblasts show defective terminal differentiation and attenuated basal autophagy when switched into differentiating culture conditions. In conclusion, we demonstrate that basal autophagy contributes to a correct execution of myogenesis and that physiological p53 activity is required for muscle homeostasis by regulating metabolism and by affecting autophagy and differentiation.

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Section: Discussionmentioning

confidence: 64%

The fine tuning of metabolism, autophagy and differentiation during in vitro myogenesis

et al. 2016

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“…The lysosomal protease Ctsd, which is itself linked to NCL by disease causing loss of function mutations [ 45 ], is slightly different in zebrafish compared to mammalian CTSD. Zebrafish Ctsd is mono-glycosylated and matures into a single-chain protein, whereas the di-glycosylated human CTSD proprotein is cleaved into a light and heavy chain [ 46 , 47 ]. However, both the proprotein and the heavy chain are increased in Grn KO mice [ 5 ], whereas zebrafish Ctsd is unchanged.…”

Section: Discussionmentioning

confidence: 99%

Granulin Knock Out Zebrafish Lack Frontotemporal Lobar Degeneration and Neuronal Ceroid Lipofuscinosis Pathology

et al. 2015

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Loss of function mutations in granulin (GRN) are linked to two distinct neurological disorders, frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL). It is so far unknown how a complete loss of GRN in NCL and partial loss of GRN in FTLD can result in such distinct diseases. In zebrafish, there are two GRN homologues, Granulin A (Grna) and Granulin B (Grnb). We have generated stable Grna and Grnb loss of function zebrafish mutants by zinc finger nuclease mediated genome editing. Surprisingly, the grna and grnb single and double mutants display neither spinal motor neuron axonopathies nor a reduced number of myogenic progenitor cells as previously reported for Grna and Grnb knock down embryos. Additionally, grna−/−;grnb−/− double mutants have no obvious FTLD- and NCL-related biochemical and neuropathological phenotypes. Taken together, the Grna and Grnb single and double knock out zebrafish lack any obvious morphological, pathological and biochemical phenotypes. Loss of zebrafish Grna and Grnb might therefore either be fully compensated or only become symptomatic upon additional challenge.

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“…The first cathepsin D related molecule that can be isolated from the cell is the diglycosylated precursor (pro Cathepsin D) of approximately 53 kDa, which can be found in the Golgi Complex and, in a variable quantity depending on the cell type and the environmental conditions, also in the extracellular space . This precursor loses the inhibitory pro‐peptide to become an enzymatic active single‐chain Intermediate of 48 kDa once it reaches the endosome, while a further processing into the mature double‐chain form takes place in the lysosome . The double chain form is made up of an N‐terminal light chain of 13 kDa and a C‐terminal heavy chain of 31–33 kDa kept together by noncovalent interactions (Fig.…”

Section: Introductionmentioning

confidence: 99%

The Role of Cathepsin D in the Pathogenesis of Human Neurodegenerative Disorders

Vidoni

Follo

Savino

et al. 2016

Medicinal Research Reviews

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123

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In familial neurodegenerative disorders, protein aggregates form continuously because of genetic mutations that drive the synthesis of truncated or unfolded proteins. The oxidative stress imposed by neurotransmitters and environmental neurotoxins constitutes an additional threat to the folding of the proteins and the integrity of organelle membranes in neurons. Failure in degrading such altered materials compromises the function of neurons and eventually leads to neurodegeneration. The lysosomal proteolytic enzyme Cathepsin D is the only aspartic-type protease ubiquitously expressed in all the cells of the human body, and it is expressed at high level in the brain. In general, cathepsin D mediated proteolysis is essential to neuronal cell homeostasis through the degradation of unfolded or oxidized protein aggregates delivered to lysosomes via autophagy or endocytosis. More specifically, many altered neuronal proteins that hallmark neurodegenerative diseases (e.g., the amyloid precursor, α-synuclein, and huntingtin) are physiologic substrates of cathepsin D and would abnormally accumulate if not efficiently degraded by this enzyme. Furthermore, experimental evidence indicates that cathepsin D activity is linked to the metabolism of cholesterol and of glycosaminoglycans, which accounts for its involvement in neuronal plasticity. This review focuses on the unique role of cathepsin D mediated proteolysis in the pathogenesis of human neurodegenerative diseases.

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Similarities and differences in the biogenesis, processing and lysosomal targeting between zebrafish and human pro-Cathepsin D: Functional implications

Cited by 6 publications

References 50 publications

The fine tuning of metabolism, autophagy and differentiation during in vitro myogenesis

The fine tuning of metabolism, autophagy and differentiation during in vitro myogenesis

Granulin Knock Out Zebrafish Lack Frontotemporal Lobar Degeneration and Neuronal Ceroid Lipofuscinosis Pathology

The Role of Cathepsin D in the Pathogenesis of Human Neurodegenerative Disorders

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