Galactocerebrosidase deficiency induces an increase in lactosylceramide content: A new hallmark of Krabbe disease?

Papini, Nadia; Giallanza, Chiara; Brioschi, L.; Ranieri, Francesca Romana; Giussani, Paola; Mauri, Laura; Ciampa, Maria Grazia; Viani, Paola; Tringali, Cristina

doi:10.1016/j.biocel.2022.106184

Cited by 9 publications

(23 citation statements)

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“…We previously identified the increase in LacCer in KD fibroblasts [ 12 ], in absence of PSY accumulation. Thus, we explored cell sphingolipid profiles during starvation to understand if changes could occur.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, we demonstrated that human KD fibroblasts are characterized by increased levels of lactosylceramide (LacCer), a substrate of GALC. In turn, LacCer is responsible for the altered activation of several signalling molecules, among which the most relevant are AKT and B-cell lymphoma 2 (BCL2), which are both upregulated [ 12 ]. Since the AKT pathway and BCL2 were shown to interact with the autophagic machinery [ 13 , 14 , 15 ], we investigated the effects of starvation to trigger autophagy in KD human fibroblasts which, as we previously reported, did not accumulate PSY [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…In turn, LacCer is responsible for the altered activation of several signalling molecules, among which the most relevant are AKT and B-cell lymphoma 2 (BCL2), which are both upregulated [ 12 ]. Since the AKT pathway and BCL2 were shown to interact with the autophagic machinery [ 13 , 14 , 15 ], we investigated the effects of starvation to trigger autophagy in KD human fibroblasts which, as we previously reported, did not accumulate PSY [ 12 ]. Our results demonstrated that, independently from PSY, KD fibroblasts showed several defects in the autophagic response and that they can be associated with AKT upregulation.…”

Section: Introductionmentioning

confidence: 99%

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Impaired Autophagy in Krabbe Disease: The Role of BCL2 and Beclin-1 Phosphorylation

Papini

Todisco

Giussani

et al. 2023

IJMS

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Autophagic impairment was identified in many lysosomal storage diseases and adult neurodegenerative diseases. It seems that this defect could be directly related to the appearance of a neurodegenerative phenotype and could contribute to worsen metabolite accumulation and lysosomal distress. Thus, autophagy is becoming a promising target for supportive therapies. Autophagy alterations were recently identified also in Krabbe disease. Krabbe disease is characterized by extensive demyelination and dysmyelination and it is due to the genetic loss of function of the lysosomal enzyme galactocerebrosidase (GALC). This enzyme leads to the accumulation of galactosylceramide, psychosine, and secondary substrates such as lactosylceramide. In this paper, we induced autophagy through starvation and examined the cellular response occurring in fibroblasts isolated from patients. We demonstrated that the inhibitory AKT-mediated phosphorylation of beclin-1 and the BCL2-beclin-1 complex concur to reduce autophagosomes formation in response to starvation. These events were not dependent on the accumulation of psychosine, which was previously identified as a possible player in autophagic impairment in Krabbe disease. We believe that these data could better elucidate the capability of response to autophagic stimuli in Krabbe disease, in order to identify possible molecules able to stimulate the process.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Impaired Autophagy in Krabbe Disease: The Role of BCL2 and Beclin-1 Phosphorylation

Papini

Todisco

Giussani

et al. 2023

IJMS

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“…Whether the GALC G 41 S mutation, and perhaps others, affecting the GALC gene directly or indirectly impact the structure and/or activity of synapses of neural networks involved in higher cognitive functions remains an open question ( Castelvetri et al, 2011 ; Cantuti Castelvetri et al, 2013 ; Cantuti-Castelvetri and Bongarzone, 2016 ; Marshall and Bongarzone, 2016 ; Gowrishankar et al, 2020 ; Rebiai et al, 2021 ) and is the subject of a follow up study in our laboratories. In addition to changes in the metabolism of psychosine, other factors such as accumulation of additional metabolites like lactosylceramide ( Papini et al, 2022 ), alteration of other signaling pathways following lipid raft rearrangements in membranes ( White et al, 2009 ; Sural-Fehr et al, 2019 ; Belleri and Presta, 2022 ), abnormal microglia-mediated synaptic pruning ( Sellgren et al, 2019 ), could be also contributors to changes in behavioral responses.…”

Section: Discussionmentioning

confidence: 99%

CRISPR-Cas9 Knock-In of T513M and G41S Mutations in the Murine β–Galactosyl-Ceramidase Gene Re-capitulates Early-Onset and Adult-Onset Forms of Krabbe Disease

Rebiai

Rue

Zaldua

et al. 2022

Front. Mol. Neurosci.

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Krabbe Disease (KD) is a lysosomal storage disorder characterized by the genetic deficiency of the lysosomal enzyme β-galactosyl-ceramidase (GALC). Deficit or a reduction in the activity of the GALC enzyme has been correlated with the progressive accumulation of the sphingolipid metabolite psychosine, which leads to local disruption in lipid raft architecture, diffuse demyelination, astrogliosis, and globoid cell formation. The twitcher mouse, the most used animal model, has a nonsense mutation, which limits the study of how different mutations impact the processing and activity of GALC enzyme. To partially address this, we generated two new transgenic mouse models carrying point mutations frequently found in infantile and adult forms of KD. Using CRISPR-Cas9 gene editing, point mutations T513M (infantile) and G41S (adult) were introduced in the murine GALC gene and stable founders were generated. We show that GALCT513M/T513M mice are short lived, have the greatest decrease in GALC activity, have sharp increases of psychosine, and rapidly progress into a severe and lethal neurological phenotype. In contrast, GALCG41S/G41S mice have normal lifespan, modest decreases of GALC, and minimal psychosine accumulation, but develop adult mild inflammatory demyelination and slight declines in coordination, motor skills, and memory. These two novel transgenic lines offer the possibility to study the mechanisms by which two distinct GALC mutations affect the trafficking of mutated GALC and modify phenotypic manifestations in early- vs adult-onset KD.

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“…Nonetheless, increasing evidence suggests that all the dysfunctions described in KD cannot be merely explained by psychosine accumulation and that additional mechanisms could be involved. In fibroblasts from KD patients, Papini et al [ 9 ] have recently correlated increased concentrations of lactosylceramide (LacCer), a bioactive lipid metabolized by GALC, to several signaling pathway alterations involved in neurodegeneration. Other studies have also reported axonal defects independent of Psy accumulation or demyelinization [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Neurodegenerative Disorder Risk in Krabbe Disease Carriers

Vantaggiato

Shaba

Carleo

et al. 2022

IJMS

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Krabbe disease (KD) is a rare autosomal recessive disorder caused by mutations in the galactocerebrosidase gene (GALC). Defective GALC causes aberrant metabolism of galactolipids present almost exclusively in myelin, with consequent demyelinization and neurodegeneration of the central and peripheral nervous system (NS). KD shares some similar features with other neuropathies and heterozygous carriers of GALC mutations are emerging with an increased risk in developing NS disorders. In this work, we set out to identify possible variations in the proteomic profile of KD-carrier brain to identify altered pathways that may imbalance its homeostasis and that may be associated with neurological disorders. The differential analysis performed on whole brains from 33-day-old twitcher (galc −/−), heterozygous (galc +/−), and wild-type mice highlighted the dysregulation of several multifunctional factors in both heterozygous and twitcher mice. Notably, the KD-carrier mouse, despite its normal phenotype, presents the deregulation of vimentin, receptor of activated protein C kinase 1 (RACK1), myelin basic protein (MBP), 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNP), transitional endoplasmic reticulum ATPase (VCP), and N-myc downstream regulated gene 1 protein (NDRG1) as well as changes in the ubiquitinated-protein pattern. Our findings suggest the carrier may be affected by dysfunctions classically associated with neurodegeneration: (i) alteration of (mechano) signaling and intracellular trafficking, (ii) a generalized affection of proteostasis and lipid metabolism, with possible defects in myelin composition and turnover, and (iii) mitochondrion and energy supply dysfunctions.

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Galactocerebrosidase deficiency induces an increase in lactosylceramide content: A new hallmark of Krabbe disease?

Cited by 9 publications

References 58 publications

Impaired Autophagy in Krabbe Disease: The Role of BCL2 and Beclin-1 Phosphorylation

Impaired Autophagy in Krabbe Disease: The Role of BCL2 and Beclin-1 Phosphorylation

CRISPR-Cas9 Knock-In of T513M and G41S Mutations in the Murine β–Galactosyl-Ceramidase Gene Re-capitulates Early-Onset and Adult-Onset Forms of Krabbe Disease

Neurodegenerative Disorder Risk in Krabbe Disease Carriers

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