Glucosylceramide Associated with Gaucher Disease Forms Amyloid-like Twisted Ribbon Fibrils That Induce α-Synuclein Aggregation

Paul, Ashim; Jacoby, Guy; Bar-Yosef, Dana Laor; Beck, Roy; Gazit, Ehud; Segal, Daniel

doi:10.1021/acsnano.1c02957

Cited by 24 publications

(26 citation statements)

References 74 publications

(193 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A direct link between GSL accumulation and alpha-synuclein fibrilisation has also been suggested. The accumulation of GlcCer has been shown to stabilise toxic alpha-synuclein oligomers and enhance its propagation in cell models of GBA deficiency [123,[170][171][172]. Lipids extracted from WT/L444P fibroblasts, but not controls, were able to accelerate the aggregation of recombinant alpha-synuclein, due to a higher content of short-chain lipids [164].…”

Section: Lipid Homeostasismentioning

confidence: 99%

GBA Variants and Parkinson Disease: Mechanisms and Treatments

Smith

Schapira

2022

Cells

View full text Add to dashboard Cite

The GBA gene encodes for the lysosomal enzyme glucocerebrosidase (GCase), which maintains glycosphingolipid homeostasis. Approximately 5–15% of PD patients have mutations in the GBA gene, making it numerically the most important genetic risk factor for Parkinson disease (PD). Clinically, GBA-associated PD is identical to sporadic PD, aside from the earlier age at onset (AAO), more frequent cognitive impairment and more rapid progression. Mutations in GBA can be associated with loss- and gain-of-function mechanisms. A key hallmark of PD is the presence of intraneuronal proteinaceous inclusions named Lewy bodies, which are made up primarily of alpha-synuclein. Mutations in the GBA gene may lead to loss of GCase activity and lysosomal dysfunction, which may impair alpha-synuclein metabolism. Models of GCase deficiency demonstrate dysfunction of the autophagic-lysosomal pathway and subsequent accumulation of alpha-synuclein. This dysfunction can also lead to aberrant lipid metabolism, including the accumulation of glycosphingolipids, glucosylceramide and glucosylsphingosine. Certain mutations cause GCase to be misfolded and retained in the endoplasmic reticulum (ER), activating stress responses including the unfolded protein response (UPR), which may contribute to neurodegeneration. In addition to these mechanisms, a GCase deficiency has also been associated with mitochondrial dysfunction and neuroinflammation, which have been implicated in the pathogenesis of PD. This review discusses the pathways associated with GBA-PD and highlights potential treatments which may act to target GCase and prevent neurodegeneration.

show abstract

Section: Lipid Homeostasismentioning

confidence: 99%

GBA Variants and Parkinson Disease: Mechanisms and Treatments

Smith

Schapira

2022

Cells

View full text Add to dashboard Cite

show abstract

“…[35] Paul et al demonstrated that the glucosylceramides associated with Gaucher disease accumulate and assemble into distorted bands that induce α-synuclein protein aggregation and stabilize the aggregation associated with the onset of Parkinson's disease. [36,37] Simple oxalic acid molecules can self-assemble into fibrous structures (Figure 5a). In another study, we injected concentrated oxalate fibers into one eye of wild type rats and compared it to the other vehicle-treated eye.…”

Section: Metabolite Assemblies In Pathological Conditionsmentioning

confidence: 99%

Minimalistic Metabolite‐Based Building Blocks for Supramolecular Functional Materials

et al. 2022

Self Cite

View full text Add to dashboard Cite

Metabolites are the set of substances produced or utilized in the biochemical process of metabolism known to perform diverse physiological functions in every living organism. As very simple molecules, metabolites can self‐assemble into functional materials for biomedical and nanotechnology applications. Simple amino acid‐based crystals exhibit interesting physicochemical properties of piezoelectricity, fluorescence and optical waveguiding. Combinations of metal‐coordinated metabolites display catalytic properties mimicking natural enzymes for chemical reactions and environmental remediation. Furthermore, excessive accumulation of metabolites spontaneously forms toxic assemblies implicated in the pathogenesis of metabolic and neurodegenerative diseases. Herein, we mainly review the progress of recent three years on the assembly of minimalistic metabolite‐based building blocks into bionanomaterials and their potential applications in energy harvesting, optical waveguiding, enzymatic catalysis, and biomedicine. We hope this review can promote the understanding and development of metabolite materials to meet functional requirements.

show abstract

“…11 Subsequently, the group also reported a yeast model for monitoring the accumulation and fibrillation of adenine. 12,13 Subsequently, Gazit research group also reported formation of amyloid like aggregates for other metabolites like quinolinic acid, 14 oxalate 15 and glucosylceramide 16 and illustrated their cytotoxic effects. [14][15][16] Hence,vmotivated by these very interesting research reports and our own interest in bio-molecular self-assembly 17.19 we were motivated to study the aggregation of urea and uric acid cycle metabolites in greater details to understand its implications in pathogenesis of diseases like HHH syndrome, Citrullinemia, Xanthinuria, Lesh Nyahn syndrome and Gout caused by caused by accumulation of metabolites.…”

Section: Introductionmentioning

confidence: 97%

Metabolite assemblies of urea cycle and uric acid pathway

Gour

Patel

Gupta

et al. 2022

Preprint

View full text Add to dashboard Cite

Herein, we report the aggregation properties of metabolites of urea cycle and uric acid pathway. The aggregation/ self-assembly properties of these metabolites were studied extensively via microscopic techniques. In this context the self-assembling properties of citrulline, ornithine, xanthine, hypoxanthine, cytosine and uracil were studied by assessing its aggregation under varying ageing time from fresh to day 15 of incubation. Interestingly, the metabolites exhibited tendency to aggregate and form soft fibril assembly during the course of ageing and gradually changes to crystalline structures on prolonged incubation. The results presented in this manuscript may have important implications in the pathogenesis of diseasescause urea and uric acid pathway metabolic dysfunction like HHH syndrome, Citrullinemia, Xanthinuria, Lesh Nyahn syndrome and Gout caused by accumulation of these metabolites.

show abstract

Glucosylceramide Associated with Gaucher Disease Forms Amyloid-like Twisted Ribbon Fibrils That Induce α-Synuclein Aggregation

Cited by 24 publications

References 74 publications

GBA Variants and Parkinson Disease: Mechanisms and Treatments

GBA Variants and Parkinson Disease: Mechanisms and Treatments

Minimalistic Metabolite‐Based Building Blocks for Supramolecular Functional Materials

Metabolite assemblies of urea cycle and uric acid pathway

Contact Info

Product

Resources

About