Lysosomal Storage Disease: Revealing Lysosomal Function and Physiology

Parkinson-Lawrence, Emma J.; Shandala, Tetyana; Prodoehl, Mark; Plew, Revecca; Borlace, Glenn N.; Brooks, Doug A.

doi:10.1152/physiol.00041.2009

Cited by 184 publications

(167 citation statements)

References 109 publications

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“…Abnormal lysosomal morphology has been described in various lysosomal storage diseases that are caused by dysfunctional amino acid efflux or impaired substrate digestion (22). Enlarged lysosomes for example, have been described in Caenorhabditis elegant qx42 mutant lacking the lysosomal lysine/arginine transporter LAAT-1, causing lysosomal amino acid accumulation (23).…”

Section: Discussionmentioning

confidence: 99%

Cystinosin-LKG rescues cystine accumulation and decreases apoptosis rate in cystinotic proximal tubular epithelial cells

et al. 2016

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Background: Nephropathic cystinosis is a lysosomal storage disease that is caused by mutations in the CTNS gene encoding a cystine/proton symporter cystinosin and an isoform cystinosin-LKG which is generated by an alternative splicing of exon 12. We have investigated the physiological role of the cystinosin-LKG that is widely expressed in epithelial tissues. Methods: We have analyzed the intracellular localization and the function of the cystinosin-LKG conjugated with DsRed (cystinosin-LKG-RFP) in Madin-Darby canine kidney cells (MDCK II) and in proximal tubular epithelial cells carrying a deletion of the CTNS gene (cystinotic PTEC), respectively. results: Cystinosin-LKG-RFP colocalized with markers of lysosomes, late endosomes and was also expressed on the apical surface of polarized MDCK II cells. Moreover, immuneelectron microscopy images of MDCK II cells overexpressing cystinosin-LKG-RFP showed stacked lamellar membranes inside perinuclear lysosomal structures. To study the role of LKG-isoform, we have investigated cystine accumulation and apoptosis that have been described in cystinotic cells. Cystinosin-LKG decreased cystine levels by approximately 10-fold similarly to cystinosin-RFP. The levels of TNFα-and actinomycin D-inducted apoptosis dropped in cystinotic cells expressing LKG-isoform. This effect was also similar to the main isoform. conclusion: Our results suggest that cystinosin-LKG and cystinosin move similar functional activities in cells.n ephropathic cystinosis (NC) is a rare lysosomal storage disease. It is caused by defective activity of cystinosin, a proton/cystine symporter that is ubiquitously expressed on lysosomal membranes, which leads to cystine accumulation into lysosomes and crystal formations in many tissues (1). One of the first symptoms of NC is renal Fanconi syndrome, secondary to a global dysfunction of proximal tubular cells. During their lifetimes, patients with NC develop several others symptoms in particular, if they are not well treated with cysteamine (2,3).Recent works have demonstrated an involvement of cystinosin in lysosomal kinetics and exocytosis (4), vesicle trafficking (4,5), autophagy, (6) and in sensing cell oxidative state (7). Studies using a cystinotic mouse model have shown decreased expression of the multi-ligand receptors megalin and cubilin in proximal tubules; this was associated with cell dedifferentiation and apoptosis (5,8). Also, enhanced cell death due to activation of proapoptotic signals probably occurs in other tissues (9-11).Cystinosin (accession number: NP_004928) is composed of seven transmembrane domains that bear two lysosomal targeting motifs (GYDQL and YFPQA) and seven N-glycosylation sites in the amino-terminal region (12). The aceview database reports various alternative splicing transcripts for the CTNS gene that encodes the cystinosin (http://www.ncbi.nlm.nih. gov/IEB/Research/Acembly). In 2008, we have identified a 400 amino acid cystinosin isoform that derives from alternative splicing of CTNS gene exon 12 (accession number: NP_001026...

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Section: Discussionmentioning

confidence: 99%

Cystinosin-LKG rescues cystine accumulation and decreases apoptosis rate in cystinotic proximal tubular epithelial cells

et al. 2016

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“…[42][43][44] Abnormalities in lysosome action or biogenesis can lead to increased apoptosis. 45,46 Lysosome impairment has also been suggested as a key mechanism in aminoglycoside antibiotic-induced nephrotoxicity. [47][48][49][50][51] Renal cell-accumulated aminoglycosides are localized primarily in endosomal and lysosomal vacuoles.…”

Section: Wwwtandfonlinecommentioning

confidence: 99%

TMBIM6 (transmembrane BAX inhibitor motif containing 6) enhances autophagy and reduces renal dysfunction in a cyclosporine A-induced nephrotoxicity model

Yadav

Lee

et al. 2015

Autophagy

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“…Lysosomal storage disorders (LSDs) are the consequence of an abnormal storage of undigested cellular debris, proteins, fats, carbohydrates, and nucleic acids within the cell (Parkinson-Lawrence et al 2010). They occur due to mutations in the genes that encode for lysosomal hydrolases, resulting in an attenuated enzyme activity and/or their transport to the lysosomes (Saftig and Klumperman 2009;Vellodi 2005).…”

Section: Introductionmentioning

confidence: 99%

Burden of Lysosomal Storage Disorders in India: Experience of 387 Affected Children from a Single Diagnostic Facility

et al. 2013

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Lysosomal storage disorders (LSDs) are considered to be a rare metabolic disease for the national health forum, clinicians, and scientists. This study aimed to know the prevalence of different LSDs, their geographical variation, and burden on the society. It included 1,110 children from January 2002 to December 2012, having coarse facial features, hepatomegaly or hepatosplenomegaly, skeletal dysplasia, neuroregression, leukodystrophy, developmental delay, cerebral-cerebellar atrophy, and abnormal ophthalmic findings. All subjects were screened for I-cell disease, glycolipid storage disorders (NiemannPick disease A/B, Gaucher), and mucopolysaccharide disorders followed by confirmatory lysosomal enzymes study from leucocytes and/or fibroblasts. Niemann-Pick disease-C (NPC) was confirmed by fibroblasts study using filipin stain. Various storage disorders were detected in 387 children (34.8 %) with highest prevalence of glycolipid storage disorders in 48 %, followed by mucopolysaccharide disorders in 22 % and defective sulfatide degradation in 14 % of the children. Less common defects were glycogen degradation defect and protein degradation defect in 5 % each, lysosomal trafficking protein defect in 4 %, and transport defect in 3 % of the patients. This study demonstrates higher incidence of Gaucher disease (16 %) followed by GM2 gangliosidosis that includes Tay-Sachs disease (10 %) and Sandhoff disease (7.8 %) and mucopolysaccharide disorders among all LSDs. Nearly 30 % of the affected children were born to consanguineous parents and this was higher (72 %) in children with Batten disease. Our study also demonstrates two common mutations c.1277_1278insTATC in 14.28 % (4/28) and c.964G>T (p.D322Y) in 10.7 % (3/28) for Tay-Sachs disease in addition to the earlier reported c.1385A>T (p.E462V) mutation in 21.42 % (6/28).

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Lysosomal Storage Disease: Revealing Lysosomal Function and Physiology

Cited by 184 publications

References 109 publications

Cystinosin-LKG rescues cystine accumulation and decreases apoptosis rate in cystinotic proximal tubular epithelial cells

Cystinosin-LKG rescues cystine accumulation and decreases apoptosis rate in cystinotic proximal tubular epithelial cells

TMBIM6 (transmembrane BAX inhibitor motif containing 6) enhances autophagy and reduces renal dysfunction in a cyclosporine A-induced nephrotoxicity model

Burden of Lysosomal Storage Disorders in India: Experience of 387 Affected Children from a Single Diagnostic Facility

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