The effect of mutant GBA1 on accumulation and aggregation of α-synuclein

Maor, Gali; Rapaport, David; Horowitz, Mia

doi:10.1093/hmg/ddz005

Cited by 34 publications

(23 citation statements)

References 65 publications

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“…Additionally, GCase-null mice were found to exhibit an accumulation of endogenous αSyn and the formation of its insoluble oligomers (Mazzulli et al, 2011;Sardi et al, 2011). Consistent with observations across multiple GBA1 model systems (Mazzulli et al, 2011;Woodard et al, 2014;Kim et al, 2018;Maor et al, 2019), we found an accumulation of both soluble and insoluble αSyn in human heterozygous-null GBA1 neurons with no change in its transcription levels. Interestingly, although the total levels of secreted αSyn remain unaffected by GCase deficiency, αSyn oligomers were selectively enriched in the conditioned media of GBA1 heterozygous-null neurons, when compared to their isogenic wild-type control.…”

Section: Discussionsupporting

confidence: 87%

LRRK2 Kinase Inhibition Rescues Deficits in Lysosome Function Due to Heterozygous GBA1 Expression in Human iPSC-Derived Neurons

et al. 2020

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Section: Discussionsupporting

confidence: 87%

LRRK2 Kinase Inhibition Rescues Deficits in Lysosome Function Due to Heterozygous GBA1 Expression in Human iPSC-Derived Neurons

et al. 2020

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“…Its aggregation would result from GCase loss-of-function and, consequently, GlcCer and/or GlcSph accumulation, as shown in PD neuronal cells [98] and in GD/PD mouse models [99]. However, this aggregation may also result from a gain-of-function effect of mutant GCase [90], which could impair the degradation of α-synuclein [100] and other misfolded proteins. These events could be due to disturbances in autophagy and proteasomal degradation [101,102].…”

Section: What Could Be the Relationship Between Glucosylceramide Gaumentioning

confidence: 99%

Are Glucosylceramide-Related Sphingolipids Involved in the Increased Risk for Cancer in Gaucher Disease Patients? Review and Hypotheses

Dubot

Astudillo

Therville

et al. 2020

Cancers

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The roles of ceramide and its catabolites, i.e., sphingosine and sphingosine 1-phosphate, in the development of malignancies and the response to anticancer regimens have been extensively described. Moreover, an abundant literature points to the effects of glucosylceramide synthase, the mammalian enzyme that converts ceramide to β-glucosylceramide, in protecting tumor cells from chemotherapy. Much less is known about the contribution of β-glucosylceramide and its breakdown products in cancer progression. In this chapter, we first review published and personal clinical observations that report on the increased risk of developing cancers in patients affected with Gaucher disease, an inborn disorder characterized by defective lysosomal degradation of β-glucosylceramide. The previously described mechanistic links between lysosomal β-glucosylceramidase, β-glucosylceramide and/or β-glucosylphingosine, and various hallmarks of cancer are reviewed. We further show that melanoma tumor growth is facilitated in a Gaucher disease mouse model. Finally, the potential roles of the β-glucosylceramidase protein and its lipidic substrates and/or downstream products are discussed.

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“…How does decreased GCase activity lead to αSyn aggregation? Several in vitro studies have shown that both GlcCer and glucosylsphingosine can directly cause monomeric αSyn to aggregate (Mazzulli et al, 2011; Taguchi et al, 2017; Maor et al, 2019). We showed a significant increase in αSyn dimers upon incubation with GlcCer-containing liposomes, which is consistent with the finding that the amount of αSyn dimers was significantly increased in erythrocytes of GD patients (Argyriou et al, 2012; Suzuki et al, 2015; Moraitou et al, 2016).…”

Section: αSyn and Lipid Metabolismmentioning

confidence: 99%

Lipids as Trans-Acting Effectors for α-Synuclein in the Pathogenesis of Parkinson’s Disease

et al. 2019

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Aggregation of α-synuclein (αSyn) plays a central role in the pathogenesis of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Lewy bodies (LBs) and Lewy neurites, which consist mainly of aggregated αSyn, are widely observed in the affected regions of patient brains. Except for some familial forms of PD/DLB, most sporadic PD/DLB patients express the wild-type (WT) αSyn protein without any mutations, and the mechanisms as to how WT αSyn gains the propensity to pathologically aggregate still remains unclear. Furthermore, the mechanisms by which the same αSyn protein can cause different synucleinopathies with distinct phenotypes and pathologies, such as PD, DLB, and multiple system atrophy (MSA), still remain largely unknown. Recently, mutations in the GBA1 gene (encoding glucocerebrosidase), which are responsible for the lysosomal storage disorder Gaucher disease (GD), have been reported to be the strongest risk factor for developing sporadic PD/DLB. We previously demonstrated that glucosylceramide accumulated by GBA1 deficiency promotes the conversion of αSyn into a proteinase K-resistant conformation. Furthermore, decreased glucocerebrosidase activity has also been reported in the brains of patients with sporadic PD/DLB. Moreover, αSyn pathology has also been shown in the brains of lysosomal storage disorder patients, which show glycosphingolipid accumulation. These observations suggest the possibility that altered lipid metabolism and lipid accumulation play roles in αSyn aggregation and PD/DLB pathogenesis. Indeed, several previous studies have demonstrated that lipid interactions affect the conformation of αSyn and induces its oligomerization and aggregation. In this review, we will give an overview of the association between αSyn aggregation and lipid interactions from the viewpoints of the etiology, pathology, and genetics of PD/DLB. We also discuss the distinct species of αSyn aggregates and their association with specific types of synucleinopathies, and introduce our hypothesis that lipid interactions play a role as trans -acting effectors in producing distinct strains of αSyn fibrils.

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The effect of mutant GBA1 on accumulation and aggregation of α-synuclein

Cited by 34 publications

References 65 publications

LRRK2 Kinase Inhibition Rescues Deficits in Lysosome Function Due to Heterozygous GBA1 Expression in Human iPSC-Derived Neurons

LRRK2 Kinase Inhibition Rescues Deficits in Lysosome Function Due to Heterozygous GBA1 Expression in Human iPSC-Derived Neurons

Are Glucosylceramide-Related Sphingolipids Involved in the Increased Risk for Cancer in Gaucher Disease Patients? Review and Hypotheses

Lipids as Trans-Acting Effectors for α-Synuclein in the Pathogenesis of Parkinson’s Disease

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