Cathepsin D Deficiency Induces Persistent Neurodegeneration in the Absence of Bax-Dependent Apoptosis

Shacka, John J.; Klocke, Barbara J.; Young, Chainllie; Shibata, Masahiro; Olney, John W.; Uchiyama, Yasuo; Säftig, Paul; Roth, Kevin A.

doi:10.1523/jneurosci.5577-06.2007

Cited by 84 publications

(62 citation statements)

References 51 publications

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“…This characteristic is reminiscent of the neuronal ceroid lipofuscinosis that is caused by CD deficiency in neuronal cells as reported by Koike et al 14 and other groups. [39][40][41] Thus, the loss of CD evoked disorders that are common to both neurons and podocytes, confirming that the two cell systems resemble each other, even under pathologic conditions in addition to normal physiologic conditions as reported previously. 42 It should be emphasized that these characteristics are closely connected to the autophagic inhibition of CD pdKO mouse podocytes.…”

Section: Discussionsupporting

confidence: 86%

Cathepsin D in Podocytes Is Important in the Pathogenesis of Proteinuria and CKD

Yamamoto-Nonaka

Koike²,

Asanuma

et al. 2016

JASN

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Studies have revealed many analogies between podocytes and neurons, and these analogies may be key to elucidating the pathogenesis of podocyte injury. Cathepsin D (CD) is a representative aspartic proteinase in lysosomes. Central nervous system neurons in CD-deficient mice exhibit a form of lysosomal storage disease with a phenotype resembling neuronal ceroid lipofuscinoses. In the kidney, the role of CD in podocytes has not been fully explored. Herein, we generated podocyte-specific CD-knockout mice that developed proteinuria at 5 months of age and ESRD by 20-22 months of age. Immunohistochemical analysis of these mice showed apoptotic podocyte death followed by proteinuria and glomerulosclerosis with aging. Using electron microscopy, we identified, in podocytes, granular osmiophilic deposits (GRODs), autophagosome/autolysosome-like bodies, and fingerprint profiles, typical hallmarks of CDdeficient neurons. CD deficiency in podocytes also led to the cessation of autolysosomal degradation and accumulation of proteins indicative of autophagy impairment and the mitochondrial ATP synthase subunit c accumulation in the GRODs, again similar to changes reported in CD-deficient neurons. Furthermore, both podocin and nephrin, two essential components of the slit diaphragm, translocated to Rab7-and lysosome-associated membrane glycoprotein 1-positive amphisomes/autolysosomes that accumulated in podocyte cell bodies in podocyte-specific CD-knockout mice. We hypothesize that defective lysosomal activity resulting in foot process effacement caused this accumulation of podocin and nephrin. Overall, our results suggest that loss of CD in podocytes causes autophagy impairment, triggering the accumulation of toxic subunit c-positive lipofuscins as well as slit diaphragm proteins followed by apoptotic cell death.

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Section: Discussionsupporting

confidence: 86%

Cathepsin D in Podocytes Is Important in the Pathogenesis of Proteinuria and CKD

Yamamoto-Nonaka

Koike²,

Asanuma

et al. 2016

JASN

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“…Because multiple types of cell death can be induced after LMP, it is not surprising that the inhibition of apoptosis after LMP has been shown to shunt the type of death to a more-necrotic nature (57). To this end, we also showed that the inhibition of Bax-dependent neuron death after lysosome dysfunction does not attenuate the degree of neuron loss or neurodegeneration (130).…”

Section: Ros Autophagy and Lysosomal Membrane Permeabilizations Deamentioning

confidence: 77%

Oxidative Stress and Autophagy in the Regulation of Lysosome-Dependent Neuron Death

Pivtoraiko

Stone

Roth

et al. 2009

Antioxidants & Redox Signaling

118

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Lysosomes critically regulate the pH-dependent catabolism of extracellular and intracellular macromolecules delivered from the endocytic/heterophagy and autophagy pathways, respectively. The importance of lysosomes to cell survival is underscored not only by their unique ability effectively to degrade metalloproteins and oxidatively damaged macromolecules, but also by the distinct potential for induction of both caspase-dependent and -independent cell death with a compromise in the integrity of lysosome function. Oxidative stress and free radical damage play a principal role in cell death induced by lysosome dysfunction and may be linked to several upstream and downstream stimuli, including alterations in the autophagy degradation pathway, inhibition of lysosome enzyme function, and lysosome membrane damage. Neurons are sensitive to lysosome dysfunction, and the contribution of oxidative stress and free radical damage to lysosome dysfunction may contribute to the etiology of neurodegenerative disease. This review provides a broad overview of lysosome function and explores the contribution of oxidative stress and autophagy to lysosome dysfunction-induced neuron death. Putative signaling pathways that either induce lysosome dysfunction or result from lysosome dysfunction or both, and the role of oxidative stress, free radical damage, and lysosome dysfunction in pediatric lysosomal storage disorders (neuronal ceroid lipofuscinoses or NCL/Batten disease) and in Alzheimer's disease are emphasized. Antioxid. Redox Signal. 11,[481][482][483][484][485][486][487][488][489][490][491][492][493][494][495][496]

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“…Autophagic stress precedes markers of apoptosis suggesting that CDdeficiency-induced lysosome dysfunction may contribute to induction of apoptosis. However, although deficiency in pro-apoptotic protein Bax clearly reduced apoptosis in CD-deficient brain, it did not alter the severity of neurodegeneration, nor attenuates autophagic stress and neuron loss suggesting an importance of caspase-independent neuron death in NCL brains [95].…”

Section: Mechanisms Of Neuronal and Retinal Cell Death In CD Knock-oumentioning

confidence: 83%

Cathepsin D—Many functions of one aspartic protease

Beneš

Větvička

Fusek

2008

Critical Reviews in Oncology/Hematology

532

474

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For years, it has been held that cathepsin D (CD) is involved in rather nonspecific protein degradation in a strongly acidic milieu of lysosomes. Studies with CD knock-out mice revealed that CD is not necessary for embryonal development but it is indispensable for postnatal tissue homeostasis. Mutation that abolishes CD enzymatic activity causes neuronal ceroid lipofuscinosis (NCL) characterized by severe neurodegeneration, developmental regression, visual loss and epilepsy in both animals and humans.In the last decade, however, an increasing number of studies demonstrated that enzymatic function of CD is not restricted solely to acidic milieu of lysosomes with important consequences in regulation of apoptosis. In addition to CD enzymatic activity, it has been shown that apoptosis is also regulated by catalytically inactive mutants of CD which suggests that CD interacts with other important molecules and influences cell signaling.Moreover, procathepsin D, secreted from cancer cells, acts as a mitogen on both cancer and stromal cells and stimulates their pro-invasive and pro-metastatic properties. Numerous studies found that pCD/CD level represents an independent prognostic factor in a variety of cancers and is therefore considered to be a potential target of anti-cancer therapy.Studies dealing with functions of cathepsin D are complicated by the fact that there are several simultaneous forms of CD in a cell -pCD, intermediate enzymatically active CD and mature heavy and light chain CD. It became evident that these forms may differently regulate the above mentioned processes.In this article, we review the possible functions of CD and its various forms in cells and organisms during physiological and pathological conditions.

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Cathepsin D Deficiency Induces Persistent Neurodegeneration in the Absence of Bax-Dependent Apoptosis

Cited by 84 publications

References 51 publications

Cathepsin D in Podocytes Is Important in the Pathogenesis of Proteinuria and CKD

Cathepsin D in Podocytes Is Important in the Pathogenesis of Proteinuria and CKD

Oxidative Stress and Autophagy in the Regulation of Lysosome-Dependent Neuron Death

Cathepsin D—Many functions of one aspartic protease

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