Role of Ceramidases in Sphingolipid Metabolism and Human Diseases

Parveen, Farzana; Bender, Daniel A.; Law, Shi‐Hui; Mishra, Vineet Kumar; Chen, Chih-Chieh; Ke, Liang‐Yin

doi:10.3390/cells8121573

Cited by 96 publications

(85 citation statements)

References 118 publications

(155 reference statements)

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“…Intriguingly, the remaining proteins are all involved in lipid degradation pathways. N-acylsphingosine amidohydrolase 1 (Asah1) hydrolyzes sphingolipid ceramides into sphingosine and free fatty acids in the lysosome [87]. N-Acylethanolamine Acid Amidase (Naaa) degrades bioactive fatty acid amides, such as N-palmitoylethanolamine [114].…”

Section: Discussionmentioning

confidence: 99%

Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

Huang

Modeste

Dammer

et al. 2020

acta neuropathol commun

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Heterozygous, loss-of-function mutations in the granulin gene (GRN) encoding progranulin (PGRN) are a common cause of frontotemporal dementia (FTD). Homozygous GRN mutations cause neuronal ceroid lipofuscinosis-11 (CLN11), a lysosome storage disease. PGRN is a secreted glycoprotein that can be proteolytically cleaved into seven bioactive 6 kDa granulins. However, it is unclear how deficiency of PGRN and granulins causes neurodegeneration. To gain insight into the mechanisms of FTD pathogenesis, we utilized Tandem Mass Tag isobaric labeling mass spectrometry to perform an unbiased quantitative proteomic analysis of whole-brain tissue from wild type (Grn+/+) and Grn knockout (Grn−/−) mice at 3- and 19-months of age. At 3-months lysosomal proteins (i.e. Gns, Scarb2, Hexb) are selectively increased indicating lysosomal dysfunction is an early consequence of PGRN deficiency. Additionally, proteins involved in lipid metabolism (Acly, Apoc3, Asah1, Gpld1, Ppt1, and Naaa) are decreased; suggesting lysosomal degradation of lipids may be impaired in the Grn−/− brain. Systems biology using weighted correlation network analysis (WGCNA) of the Grn−/− brain proteome identified 26 modules of highly co-expressed proteins. Three modules strongly correlated to Grn deficiency and were enriched with lysosomal proteins (Gpnmb, CtsD, CtsZ, and Tpp1) and inflammatory proteins (Lgals3, GFAP, CD44, S100a, and C1qa). We find that lysosomal dysregulation is exacerbated with age in the Grn−/− mouse brain leading to neuroinflammation, synaptic loss, and decreased markers of oligodendrocytes, myelin, and neurons. In particular, GPNMB and LGALS3 (galectin-3) were upregulated by microglia and elevated in FTD-GRN brain samples, indicating common pathogenic pathways are dysregulated in human FTD cases and Grn−/− mice. GPNMB levels were significantly increased in the cerebrospinal fluid of FTD-GRN patients, but not in MAPT or C9orf72 carriers, suggesting GPNMB could be a biomarker specific to FTD-GRN to monitor disease onset, progression, and drug response. Our findings support the idea that insufficiency of PGRN and granulins in humans causes neurodegeneration through lysosomal dysfunction, defects in autophagy, and neuroinflammation, which could be targeted to develop effective therapies.

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Section: Discussionmentioning

confidence: 99%

Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

Huang

Modeste

Dammer

et al. 2020

acta neuropathol commun

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“…It is ubiquitously expressed and is localized to the lysosome to maintain intralysosomal ceramide homeostasis. 2 When deficient, ceramides accumulate inside lysosomes of various tissues. The most common phenotype of ASAH1 defects is Farber granulomatosis (OMIM 228000), which is characterized by the clinical triad of subcutaneous nodules, joint pain/contractures, and voice hoarseness, 3 in addition to various combinations of organomegaly, respiratory, skeletal and neurological manifestations.…”

Section: Introductionmentioning

confidence: 99%

ASAH1‐related disorders: Description of 15 novel pediatric patients and expansion of the clinical phenotype

et al. 2020

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Acid ceramidase deficiency is an orphan lysosomal disorder caused by ASAH1 pathogenic variants and presenting with either Farber disease or spinal muscle atrophy with progressive myoclonic epilepsy (SMA-PME). Phenotypic and genotypic features are rarely explored beyond the scope of case reports. Furthermore, the new biomarker C26-Ceramide requires validation in a clinical setting. We evaluated the clini

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“…There are three isoforms of CDase classified, like SMases, according to their optimal pH of function and their subcellular location. Acid CDase (ASAH1) is localized in lysosomes and is more effective in deacylating medium-chain ceramides (C12-and C14-rather than C16-and C18-ceramide) (4,25). Neutral CDase (ASAH2) is an important regulator for the production of sphingosine and S1P at the plasma membrane (4,25).…”

Section: Sphingomyelinase and Ceramidase Pathwaysmentioning

confidence: 99%

“…ACER3 is a phytoceramidase that is localized in both the RE and the Golgi. It is expressed in many tissues, its most important expression being found in the placenta, like ACER2 (4,25). Interestingly, sphingosine is considered to be exclusively generated from ceramide through the action of CDase.…”

Section: Sphingomyelinase and Ceramidase Pathwaysmentioning

confidence: 99%

Sphingolipid Metabolism and Signaling in Skeletal Muscle: From Physiology to Physiopathology

et al. 2020

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Sphingolipids represent one of the major classes of eukaryotic lipids. They play an essential structural role, especially in cell membranes where they also possess signaling properties and are capable of modulating multiple cell functions, such as apoptosis, cell proliferation, differentiation, and inflammation. Many sphingolipid derivatives, such as ceramide, sphingosine-1-phosphate, and ganglioside, have been shown to play many crucial roles in muscle under physiological and pathological conditions. This review will summarize our knowledge of sphingolipids and their effects on muscle fate, highlighting the role of this class of lipids in modulating muscle cell differentiation, regeneration, aging, response to insulin, and contraction. We show that modulating sphingolipid metabolism may be a novel and interesting way for preventing and/or treating several muscle-related diseases.

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Role of Ceramidases in Sphingolipid Metabolism and Human Diseases

Cited by 96 publications

References 118 publications

Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

ASAH1‐related disorders: Description of 15 novel pediatric patients and expansion of the clinical phenotype

Sphingolipid Metabolism and Signaling in Skeletal Muscle: From Physiology to Physiopathology

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