Lipid composition of microdomains is altered in neuronopathic Gaucher disease sheep brain and spleen

Hein, Leanne K.; Rozaklis, Tina; Adams, Melissa; Hopwood, John J.; Karageorgos, Litsa

doi:10.1016/j.ymgme.2017.05.010

Cited by 16 publications

(9 citation statements)

References 51 publications

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“…Understanding the interaction between gangliosides lipids and α-syn is therefore highly relevant. Association between ganglioside lipids, PD and Gaucher disease has been demonstrated [69, 70]. Gaucher disease is the most common lysosomal storage disease and is caused by deficiency of the lysosomal enzyme glucocerebrosidase, resulting in accumulation of glycolipids.…”

Section: Discussionmentioning

confidence: 99%

Ganglioside lipids accelerate α-synuclein amyloid formation

Gaspar

Pallbo

Weininger

et al. 2018

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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The deposition of α-synuclein fibrils is one hallmark of Parkinson's disease. Here, we investigate how ganglioside lipids, present in high amounts in neurons and exosomes, influence the aggregation kinetics of α-synuclein. Gangliosides, as well as, other anionic lipid species with small or large headgroups were found to induce conformational changes of α-synuclein monomers and catalyse their aggregation at mildly acidic conditions. Although the extent of this catalytic effect was slightly higher for gangliosides, the results imply that charge interactions are more important than headgroup chemistry in triggering aggregation. In support of this idea, uncharged lipids with large headgroups were not found to induce any conformational change and only weakly catalyse aggregation. Intriguingly, aggregation was also triggered by free ganglioside headgroups, while these caused no conformational change of α-synuclein monomers. Our data reveal that partially folded α-synuclein helical intermediates are not required species in triggering of α-synuclein aggregation.

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Section: Discussionmentioning

confidence: 99%

Ganglioside lipids accelerate α-synuclein amyloid formation

Gaspar

Pallbo

Weininger

et al. 2018

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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“…In Parkinson’s disease, the mutation of the protein DJ-1, which is associated with rafts in astrocytes, results in raft disruption and consequent glutamatergic signaling disruption [ 275 ]. Lipid domains are also affected in lipid-related diseases (e.g., Krabbe disease), where a defective enzymatic activity leads to altered lipid raft signaling pathways [ 179 , 276 ].…”

Section: Microvesicle Biogenesis and Shedding—role Of Plasma Membrmentioning

confidence: 99%

Plasma Membrane Lipid Domains as Platforms for Vesicle Biogenesis and Shedding?

et al. 2018

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Extracellular vesicles (EVs) contribute to several pathophysiological processes and appear as emerging targets for disease diagnosis and therapy. However, successful translation from bench to bedside requires deeper understanding of EVs, in particular their diversity, composition, biogenesis and shedding mechanisms. In this review, we focus on plasma membrane-derived microvesicles (MVs), far less appreciated than exosomes. We integrate documented mechanisms involved in MV biogenesis and shedding, focusing on the red blood cell as a model. We then provide a perspective for the relevance of plasma membrane lipid composition and biophysical properties in microvesiculation on red blood cells but also platelets, immune and nervous cells as well as tumor cells. Although only a few data are available in this respect, most of them appear to converge to the idea that modulation of plasma membrane lipid content, transversal asymmetry and lateral heterogeneity in lipid domains may play a significant role in the vesiculation process. We suggest that lipid domains may represent platforms for inclusion/exclusion of membrane lipids and proteins into MVs and that MVs could originate from distinct domains during physiological processes and disease evolution.

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“…Genetic analysis revealed homozygous missense mutations in the ovine GBA gene, which in human patients leads to an acute neuronopathic, or Type II, phenotype. Sheep with neuronopathic Gaucher disease have been invaluable in studying lipid homeostasis and cellular membrane composition in neurodegenerative disease states in a large animal model ( 53 , 54 ). However, sheep with Gaucher disease typically die within a few days of birth therefore establishing a research flock to study disease progression or assess long-term efficacy of potential therapeutics is not an option.…”

Section: Naturally Occurring Sheep Disease Modelsmentioning

confidence: 99%

The Translational Benefits of Sheep as Large Animal Models of Human Neurological Disorders

Murray

Mitchell

2022

Front. Vet. Sci.

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The past two decades have seen a considerable rise in the use of sheep to model human neurological disorders. While each animal model has its merits, sheep have many advantages over small animal models when it comes to studies on the brain. In particular, sheep have brains more comparable in size and structure to the human brain. They also have much longer life spans and are docile animals, making them useful for a wide range of in vivo studies. Sheep are amenable to regular blood and cerebrospinal fluid sampling which aids in biomarker discovery and monitoring of treatment efficacy. Several neurological diseases have been found to occur naturally in sheep, however sheep can also be genetically engineered or experimentally manipulated to recapitulate disease or injury. Many of these types of sheep models are currently being used for pre-clinical therapeutic trials, particularly gene therapy, with studies from several models culminating in potential treatments moving into clinical trials. This review will provide an overview of the benefits of using sheep to model neurological conditions, and highlight naturally occurring and experimentally induced sheep models that have demonstrated translational validity.

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Lipid composition of microdomains is altered in neuronopathic Gaucher disease sheep brain and spleen

Cited by 16 publications

References 51 publications

Ganglioside lipids accelerate α-synuclein amyloid formation

Ganglioside lipids accelerate α-synuclein amyloid formation

Plasma Membrane Lipid Domains as Platforms for Vesicle Biogenesis and Shedding?

The Translational Benefits of Sheep as Large Animal Models of Human Neurological Disorders

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