Secondary biochemical and morphological consequences in lysosomal storage diseases

Alroy, Joseph; Garganta, Cheryl; Wiederschain, G.Ya.

doi:10.1134/s0006297914070049

Cited by 19 publications

(15 citation statements)

References 143 publications

(117 reference statements)

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“…These less electron-dense lysosomes might represent lysosomes in which digestion of the contents is perturbed, as the normally dark lumen is a result of enzymes actively degrading the material in acidic lysosomal interior (31). Similar observations of enlarged and electron-lucent lysosomal vacuoles are described in lysosomal storage disorders (50)(51)(52). Supporting this notion, the overall lysosomal enzyme activity was significantly decreased in the PARK2 KO neurons.…”

Section: Cccp-treated Control Neurons Contained Almost Equal Numbers supporting

confidence: 60%

Lysosomal perturbations in dopaminergic neurons derived from induced pluripotent stem cells with PARK2 mutation

Okarmus

Bogetofte

Schmidt

et al. 2019

Preprint

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Mutations in the PARK2 gene encoding parkin, an E3 ubiquitin ligase, are associated with autosomal recessive early-onset Parkinson's disease (PD). While parkin has been implicated in the regulation of mitophagy and proteasomal degradation, the precise mechanism leading to neurodegeneration in both sporadic and familial PD upon parkin loss-of-function mutations remains unknown. Cultures of isogenic induced pluripotent stem cell (iPSC) lines with and without PARK2 knockout (KO) enable mechanistic studies of the effect of parkin deficiency in human dopaminergic neurons. In the present study, we used such cells to investigate the impact of PARK2 KO on the lysosomal compartment combining different approaches, such as mass spectrometry-based proteomics, electron microscopy (TEM) analysis and functional assays. We discovered a clear link between parkin deficiency and lysosomal alterations. PARK2 KO neurons exhibited a perturbed lysosomal morphology, displaying significantly enlarged and electron-lucent lysosomes as well as an increased total lysosomal content, which was exacerbated by mitochondrial stress. In addition, we found perturbed autophagic flux and decreased lysosomal enzyme activity suggesting an impairment of the autophagylysosomal pathway in parkin-deficient cells. Interestingly, activity of the GBA-encoded enzyme, b-glucocerebrosidase, was significantly increased suggesting the existence of a compensatory mechanism. In conclusion, our data provide a unique characterization of the morphology, content, and function of lysosomes in PARK2 KO neurons, thus revealing a new important connection between mitochondrial dysfunction and lysosomal dysregulation in PD pathogenesis.

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Section: Cccp-treated Control Neurons Contained Almost Equal Numbers supporting

confidence: 60%

Lysosomal perturbations in dopaminergic neurons derived from induced pluripotent stem cells with PARK2 mutation

Okarmus

Bogetofte

Schmidt

et al. 2019

Preprint

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“…As mentioned above, LSDs are characterized by autophagy impairment, which also takes place in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and Niemann-Pick [6,29–31]. Recently, tremendous progress has been made in characterizing the autophagy protein machinery and signalling cascades, resulting in an explosion of applied research in autophagy [32].…”

Section: Discussionmentioning

confidence: 99%

Defective Autophagy, Mitochondrial Clearance and Lipophagy in Niemann-Pick Type B Lymphocytes

et al. 2016

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Niemann-Pick disease type A (NP-A) and type B (NP-B) are lysosomal storage diseases (LSDs) caused by sphingomyelin accumulation in lysosomes relying on reduced or absent acid sphingomyelinase. A considerable body of evidence suggests that lysosomal storage in many LSD impairs autophagy, resulting in the accumulation of poly-ubiquitinated proteins and dysfunctional mitochondria, ultimately leading to cell death. Here we test this hypothesis in a cellular model of Niemann-Pick disease type B, in which autophagy has never been studied. The basal autophagic pathway was first examined in order to evaluate its functionality using several autophagy-modulating substances such as rapamycin and nocodazole. We found that human NP-B B lymphocytes display considerable alteration in their autophagic vacuole accumulation and mitochondrial fragmentation, as well as mitophagy induction (for damaged mitochondria clearance). Furthermore, lipid traceability of intra and extra-cellular environments shows lipid accumulation in NP-B B lymphocytes and also reveals their peculiar trafficking/management, culminating in lipid microparticle extrusion (by lysosomal exocytosis mechanisms) or lipophagy. All of these features point to the presence of a deep autophagy/mitophagy alteration revealing autophagic stress and defective mitochondrial clearance. Hence, rapamycin might be used to regulate autophagy/mitophagy (at least in part) and to contribute to the clearance of lysosomal aberrant lipid storage.

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“…The most usual classification of LSDs is based on the type of material that is accumulated. LSDs are divided in sphingolipidoses (accumulation of sphingolipids), mucopolysaccharidoses (accumulation of glycosaminoglycans), mucolipidoses (accumulation of glycolipids, glycosaminoglycans, and oligosaccharides), and glycoproteinoses (accumulation of glycoproteins) [4]. The most common LSDs are sphingolipidoses, which are usually characterized by the accumulation of glycosphingolipids (GSLs): ceramide or sphingosine molecules modified by the addition of sugar head groups.…”

Section: Introductionmentioning

confidence: 99%

From Lysosomal Storage Diseases to NKT Cell Activation and Back

Pereira

Ribeiro

Macedo

2017

IJMS

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Lysosomal storage diseases (LSDs) are inherited metabolic disorders characterized by the accumulation of different types of substrates in the lysosome. With a multisystemic involvement, LSDs often present a very broad clinical spectrum. In many LSDs, alterations of the immune system were described. Special emphasis was given to Natural Killer T (NKT) cells, a population of lipid-specific T cells that is activated by lipid antigens bound to CD1d (cluster of differentiation 1 d) molecules at the surface of antigen-presenting cells. These cells have important functions in cancer, infection, and autoimmunity and were altered in a variety of LSDs’ mouse models. In some cases, the observed decrease was attributed to defects in either lipid antigen availability, trafficking, processing, or loading in CD1d. Here, we review the current knowledge about NKT cells in the context of LSDs, including the alterations detected, the proposed mechanisms to explain these defects, and the relevance of these findings for disease pathology. Furthermore, the effect of enzyme replacement therapy on NKT cells is also discussed.

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Secondary biochemical and morphological consequences in lysosomal storage diseases

Cited by 19 publications

References 143 publications

Lysosomal perturbations in dopaminergic neurons derived from induced pluripotent stem cells with PARK2 mutation

Lysosomal perturbations in dopaminergic neurons derived from induced pluripotent stem cells with PARK2 mutation

Defective Autophagy, Mitochondrial Clearance and Lipophagy in Niemann-Pick Type B Lymphocytes

From Lysosomal Storage Diseases to NKT Cell Activation and Back

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