Lysosome dysfunction in the pathogenesis of kidney diseases

Surendran, Kameswaran; Vitiello, Seasson Phillips; Pearce, David A.

doi:10.1007/s00467-013-2652-z

Cited by 48 publications

(32 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…; Surendran et al . ). During the course of these studies, we identified a novel phenotype in Cln3 Δex7/8 mice, namely significant reductions in whisker length beginning at 4 months of age and progressively decreasing out to 12 months (Fig.…”

Section: Resultsmentioning

confidence: 97%

Caspase 1 activity influences juvenile Batten disease (CLN3) pathogenesis

Burkovetskaya

Bosch

Karpuk

et al. 2018

Journal of Neurochemistry

View full text Add to dashboard Cite

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is an autosomal recessive lysosomal storage disease caused by loss-of-function mutations in CLN3. Symptoms appear between 5 and 10 years of age, beginning with blindness and seizures, followed by progressive cognitive and motor decline, and premature death. Glial activation and impaired neuronal activity are early signs of pathology in the Cln3 mouse model of JNCL, whereas neuron death occurs much later in the disease process. We previously reported that Cln3 microglia are primed toward a pro-inflammatory phenotype typified by exaggerated caspase 1 inflammasome activation and here we extend those findings to demonstrate heightened caspase activity in the Cln3 mouse brain. Based on the ability of caspase 1 to cleave a large number of substrates that have been implicated in JNCL pathology, we examined the functional implications of caspase 1 inflammasome activity by crossing Cln3 and caspase 1-deficient mice to create Cln3 /Casp-1 animals. Caspase 1 deletion influenced motor behavior deficits and astrocyte activation in the context of CLN3 mutation, since both were significantly reversed in Cln3 /Casp-1 mice, with phenotypes approaching that of wild-type animals. We also report a progressive age-dependent reduction in whisker length in Cln3 mice that was partially caspase 1-dependent. However, not all CLN3 phenotypes were reversed following caspase 1 deletion, since no significant differences in lysosomal accumulation or microglial activation were observed between Cln3 and Cln3 /Casp-1 mice. Although the molecular targets of aberrant caspase 1 activity in the context of CLN3 mutation remain to be identified, our studies suggest that caspase 1 may represent a potential therapeutic target to mitigate some attributes of CLN3 disease. This article is part of the Special Issue "Lysosomal Storage Disorders".

show abstract

Section: Resultsmentioning

confidence: 97%

Caspase 1 activity influences juvenile Batten disease (CLN3) pathogenesis

Burkovetskaya

Bosch

Karpuk

et al. 2018

Journal of Neurochemistry

View full text Add to dashboard Cite

show abstract

“…65 Lysosomes are acidic organelles that play an important role in macromolecule degradation and recycling. Fabry disease (MIM: 301500), cystinosis (MIM: 219800), and neuronal ceroid (E) Edema rate of zebrafish after nfkb1 and manba knockdown; p values were calculated for each concentration group using Fisher's exact test.…”

Section: Discussionmentioning

confidence: 99%

“…[65][66][67] Many lysosomal enzyme mutations present with primary central nervous system defects, and these mutations are also associated with altered kidney function and ultimately lead to CKD. Renal tubules reabsorb more than 100 L of fluid and large amounts of organic and inorganic matter to maintain homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease

Qiu

et al. 2017

The American Journal of Human Genetics

View full text Add to dashboard Cite

Chronic kidney disease (CKD) is a complex gene-environmental disease affecting close to 10% of the US population. Genome-wide association studies (GWASs) have identified sequence variants, localized to non-coding genomic regions, associated with kidney function. Despite these robust observations, the mechanism by which variants lead to CKD remains a critical unanswered question. Expression quantitative trait loci (eQTL) analysis is a method to identify genetic variation associated with gene expression changes in specific tissue types. We hypothesized that an integrative analysis combining CKD GWAS and kidney eQTL results can identify candidate genes for CKD. We performed eQTL analysis by correlating genotype with RNA-seq-based gene expression levels in 96 human kidney samples. Applying stringent statistical criteria, we detected 1,886 genes whose expression differs with the sequence variants. Using direct overlap and Bayesian methods, we identified new potential target genes for CKD. With respect to one of the target genes, lysosomal beta A mannosidase (MANBA), we observed that genetic variants associated with MANBA expression in the kidney showed statistically significant colocalization with variants identified in CKD GWASs, indicating that MANBA is a potential target gene for CKD. The expression of MANBA was significantly lower in kidneys of subjects with risk alleles. Suppressing manba expression in zebrafish resulted in renal tubule defects and pericardial edema, phenotypes typically induced by kidney dysfunction. Our analysis shows that gene-expression changes driven by genetic variation in the kidney can highlight potential new target genes for CKD development.

show abstract

“…As an essential organelle, the lysosome, within approximately 50 hydrolases, is responsible for the degradation and recycling of macromolecules 33 34 . Thiols are closely associated with proteolysis in the lysosome which reduces disulphide bonds 35 .…”

mentioning

confidence: 99%

A Two-Photon Fluorescent Probe for Lysosomal Thiols in Live Cells and Tissues

Fan

Han

Yao

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Lysosome-specific fluorescent probes are exclusive to elucidate the functions of lysosomal thiols. Moreover, two-photon microscopy offers advantages of less phototoxicity, better three dimensional spatial localization, deeper penetration depth and lower self-absorption. However, such fluorescent probes for thiols are still rare. In this work, an efficient two-photon fluorophore 1,8-naphthalimide-based probe conjugating a 2,4-dinitrobenzenesulfonyl chloride and morpholine was designed and synthesized, which exhibited high selectivity and sensitivity towards lysosomal thiols by turn-on fluorescence method quantitatively and was successfully applied to the imaging of thiols in live cells and tissues by two-photon microscopy.

show abstract

Lysosome dysfunction in the pathogenesis of kidney diseases

Cited by 48 publications

References 84 publications

Caspase 1 activity influences juvenile Batten disease (CLN3) pathogenesis

Caspase 1 activity influences juvenile Batten disease (CLN3) pathogenesis

Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease

A Two-Photon Fluorescent Probe for Lysosomal Thiols in Live Cells and Tissues

Contact Info

Product

Resources

About