Impaired proteolysis underlies autophagic dysfunction in Niemann–Pick type C disease

Elrick, Matthew J.; Yu, Ting; Chung, CH; Lieberman, Andrew P.

doi:10.1093/hmg/dds324

Cited by 133 publications

(135 citation statements)

References 68 publications

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“…27 Using human embryonic stem cell-derived neurons, it was shown that both induction of basal autophagy and impaired autophagic flux concomitantly occur with NPC1 knockdown and that this significantly compromises mitochondrial clearance. 26 Remarkably, these changes were partially reversible through the application of the autophagy inhibitor 3-methyladenine, which reduces autophagosome formation and, by treatment with cyclodextrin, a compound capable of mobilizing cholesterol from the lysosomal compartment.…”

Section: Reviewmentioning

confidence: 99%

Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases

et al. 2013

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Pediatric neurodegenerative diseases are a heterogeneous group of diseases that result from specific genetic and biochemical defects. In recent years, studies have revealed a wide spectrum of abnormal cellular functions that include impaired proteolysis, abnormal lipid trafficking, accumulation of lysosomal content, and mitochondrial dysfunction. Within neurons, elaborated degradation pathways such as the ubiquitin-proteasome system and the autophagy-lysosomal pathway are critical for maintaining homeostasis and normal cell function. Recent evidence suggests a pivotal role for autophagy in major adult and pediatric neurodegenerative diseases. We herein review genetic, pathological, and molecular evidence for the emerging link between autophagy dysfunction and lysosomal storage disorders such as Niemann-Pick type C, progressive myoclonic epilepsies such as Lafora disease, and leukodystrophies such as Alexander disease. We also discuss the recent discovery of genetically deranged autophagy in Vici syndrome, a multisystem disorder, and the implications for the role of autophagy in development and disease. Deciphering the exact mechanism by which autophagy contributes to disease pathology may open novel therapeutic avenues to treat neurodegeneration. To this end, an outlook on novel therapeutic approaches targeting autophagy concludes this review. P ediatric neurodegenerative diseases are a heterogeneous group of diseases that result from specific genetic and biochemical defects. Although the age of onset and the clinical course are variable, neurodegenerative disorders of childhood are characterized by progressive neurologic and cognitive dysfunction with loss of speech, vision, hearing, and motor skills, and a frequent association with seizures, feeding difficulties, and failure to thrive. The degenerative process can affect white and gray matter and spreads in a disease-specific manner. Current genetic and biochemical testing and neuroimaging can establish a diagnosis. The outcome for most diseases, however, is still poor, as therapeutic approaches are limited.Accumulation of proteins, polysaccharides, and lipids are common mechanisms shared by major adult-onset neurodegenerative diseases 1-3 and many neurodegenerative diseases of childhood. 4 These conditions are, therefore, often referred to as "storage diseases" or "proteinopathies. " Cells and postmitotic cells such as neurons, in particular, rely on effective cargo targeting, tagging, transportation, and degradation to maintain intracellular homeostasis under normal conditions and metabolic stress. Within this network, autophagy plays an indispensible role by eliminating misfolded and aggregated proteins, lipids, saccharides, and damaged organelles. Recent evidence suggests that autophagy is dysregulated in a number of pediatric neurodegenerative and metabolic diseases. AUTOPHAGY: AN OVERVIEWAutophagy describes intracellular pathways that converge into degradation of target material in lysosomes. 5 The route of cargo delivery to the lysosome distinguishes th...

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Section: Reviewmentioning

confidence: 99%

Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases

et al. 2013

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“…It has been proposed that altered lipid content (i.e., high cholesterol or ganglioside levels) may contribute to autophagy impairment. [20][21][22][23][24] On the other hand, the lipid that most significantly accumulates in neurons from ASMko mice is SM. 10 Hence, we directly tested whether SM accumulation was responsible for the autophagosome-lysosome alterations observed in the ASMko mice brain.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, ASMko mice brains show cholesterol deposits 29,30 and the accumulation of this lipid impairs lysosomal function in different LSDs. 21,22,24 To test cholesterol involvement, NPA fibroblasts were incubated with methyl-b-cyclodextrin, which sequesters this lipid without affecting SM. 31 Treatment for 24 h with 0.3 mM methyl-b-cyclodextrin had no effect on LC3-II levels ( Figure 5c) despite its efficiency in reducing cholesterol levels by 16% (Figure 5d), similar to the 15% SM reduction promoted by FB1.…”

Section: Resultsmentioning

confidence: 99%

“…Magic Red staining in fibroblasts plated in Borosilicate chambers (Nunc, Lab-Tek, Thermo Scientific, Rochester, NY, USA) was performed. 22 Cytosolic extracts. For cytosol extraction, fibroblasts or neurons were incubated in HEPES buffer pH 7.5 containing 15 mg/ml of Digitonin (Sigma-Aldrich).…”

Section: Methodsmentioning

confidence: 99%

“…Among the lysosomal proteases, Cathepsin B has a broad specificity for peptide bonds and has a major role in intracellular protein degradation. 33 These features together with the proposed role of stored lipids in the direct inhibition of this protease 22 and its enhanced expression in hepatic cells from ASMko mice 34 moved us to analyze it in detail. We did not find significant differences in Cathepsin B levels in control and NPA fibroblasts (Figure 7a).…”

Section: Protein (Egfp)mentioning

confidence: 99%

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High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

et al. 2014

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Niemann Pick disease type A (NPA), which is caused by loss of function mutations in the acid sphingomyelinase (ASM) gene, is a lysosomal storage disorder leading to neurodegeneration. Yet, lysosomal dysfunction and its consequences in the disease are poorly characterized. Here we show that undegraded molecules build up in neurons of acid sphingomyelinase knockout mice and in fibroblasts from NPA patients in which autophagolysosomes accumulate. The latter is not due to alterations in autophagy initiation or autophagosome-lysosome fusion but because of inefficient autophago-lysosomal clearance. This, in turn, can be explained by lysosomal membrane permeabilization leading to cytosolic release of Cathepsin B. High sphingomyelin (SM) levels account for these effects as they can be induced in control cells on addition of the lipid and reverted on SM-lowering strategies in ASM-deficient cells. These results unveil a relevant role for SM in autophagy modulation and characterize autophagy anomalies in NPA, opening new perspectives for therapeutic interventions.

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Late‐onset Krabbe disease presenting as spastic paraplegia – implications of GCase and CTSB/D

Mächtel,

Dobert,

Hehr

et al. 2024

Ann Clin Transl Neurol

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ObjectiveKrabbe disease (KD) is a multisystem neurodegenerative disorder with severe disability and premature death, mostly with an infancy/childhood onset. In rare cases of late‐onset phenotypes, symptoms are often milder and difficult to diagnose. We here present a translational approach combining diagnostic and biochemical analyses of a male patient with a progressive gait disorder starting at the age of 44 years, with a final diagnosis of late‐onset KD (LOKD).MethodsAdditionally to cerebral MRI, protein structural analyses of the β‐galactocerebrosidase protein (GALC) were performed. Moreover, expression, lysosomal localization, and activities of β‐glucocerebrosidase (GCase), cathepsin B (CTSB), and cathepsin D (CTSD) were analyzed in leukocytes, fibroblasts, and lysosomes of fibroblasts.ResultsExome sequencing revealed biallelic likely pathogenic variants: GALC exons 11–17: 33 kb deletion; exon 4: missense variant (c.334A>G, p.Thr112Ala). We detected a reduced GALC activity in leukocytes and fibroblasts. While histological KD phenotypes were absent in fibroblasts, they showed a significantly decreased activities of GCase, CTSB, and CTSD in lysosomal fractions, while expression levels were unaffected.InterpretationThe presented LOKD case underlines the age‐dependent appearance of a mildly pathogenic GALC variant and its interplay with other lysosomal proteins. As GALC malfunction results in reduced ceramide levels, we assume this to be causative for the here described decrease in CTSB and CTSD activity, potentially leading to diminished GCase activity. Hence, we emphasize the importance of a functional interplay between the lysosomal enzymes GALC, CTSB, CTSD, and GCase, as well as between their substrates, and propose their conjoined contribution in KD pathology.

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Impaired proteolysis underlies autophagic dysfunction in Niemann–Pick type C disease

Cited by 133 publications

References 68 publications

Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases

Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

Late‐onset Krabbe disease presenting as spastic paraplegia – implications of GCase and CTSB/D

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