Neuronopathic GBA1 L444P mutation accelerates Glucosylsphingosine levels and formation of hippocampal alpha-synuclein inclusions

Mahoney-Crane, Casey L.; Viswanathan, Megha; Russell, Drèson L.; Curtiss, Rachel A.C.; Freire, Jennifer; Bobba, Sai Sumedha; Coyle, Sean D.; Kandebo, Monika; Yao, Lihang; Wan, Bin-Lin; Hatcher, Nathan G.; Smith, Sean M.; Marcus, Jacob; Volpicelli‐Daley, Laura A.

doi:10.1101/2022.04.07.487391

Cited by 2 publications

(1 citation statement)

References 59 publications

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“…Human iPSCs are well-established systems for in vitro disease modeling. The homozygous GBA1 L444P mutation is described to cause a severe form of GD with greatly decreased GCase levels and has been identified as PD risk gene with 5.6-fold increased risk of cognitive impairments [21,[65][66][67]. Our previously established iPSC-derived DA (iPS-DA) neurons carrying GBA1 L444P biallelic mutations (L444P/L444P) [56] show reduced GCase protein levels (46.6 µg/mg protein in WT vs 6.9 µg/mg protein in L444P) and increased GlcSph accumulation (~3 folds) (Figs 2A and 2B).…”

Section: In Vitro and In Vivo Gd Phenotype Was Rescued By Aav5 Or Aav...mentioning

confidence: 99%

AAV delivery ofGBA1suppresses α-synuclein accumulation in Parkinson’s disease models and restores motor dysfunction in a Gaucher’s disease model

Okai,

Sato,

Deshpande

et al. 2024

Preprint

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Biallelic mutations in theglucosylceramidase beta 1(GBA1) gene are the underlying genetic cause of Gaucher’s disease (GD), resulting in a deficient lysosomal hydrolase and subsequent accumulation of glycosphingolipids. More recently,GBA1mutations have been identified as the most prevalent genetic risk factor for Parkinson’s disease (PD), associated with more pronounced symptoms characterized by earlier onset and accelerated cognitive decline. In these GBA-associated PD patients the α-synuclein pathology is more prominent, and recent data suggest a link between α-synucleinopathies andGBA1mutations. Here, we explored the effect ofGBA1gene supplementation on the GD phenotypes and α-synuclein pathology by using the adeno-associated virus (AAV) system. We have compared two AAV serotypes, AAV5 and AAV9, and two different ubiquitous promoters, and demonstrate that both promoters work efficiently albeit not the samein vitroandin vivo. GBA1overexpression reduces the accumulation of glucosylsphingosine (GlcSph) and restores motor dysfunction in a GD mouse model. We further demonstrate thatGBA1overexpression can dissolve phospho-α-synuclein aggregation induced by the addition of α-synuclein pre-formed fibril (PFF) in a mouse primary neuron model suggesting the direct effect of β-Glucocerebrosidase (GCase) on α-synuclein accumulation.In vivo, we show that GCase inhibition can induce insoluble high-molecular-weight α-synuclein aggregation and that delivery ofGBA1achieves robust reduction of the α-synuclein aggregates in the mouse brain. In summary, GCase expression not only reduces GlcSph, but also restores GD motor dysfunction and removes α-synuclein aggregates which are the hallmark for PD and α-synucleinopathies. AAV delivery ofGBA1is a powerful approach to restore glucocerebrosidase function and to resolve misfolded α-synuclein protein, with applications for GD and PD.

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Section: In Vitro and In Vivo Gd Phenotype Was Rescued By Aav5 Or Aav...mentioning

confidence: 99%

AAV delivery ofGBA1suppresses α-synuclein accumulation in Parkinson’s disease models and restores motor dysfunction in a Gaucher’s disease model

Okai,

Sato,

Deshpande

et al. 2024

Preprint

View full text Add to dashboard Cite

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Genetic variations in GBA1 and LRRK2 genes: Biochemical and clinical consequences in Parkinson disease

et al. 2022

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Variants in the GBA1 and LRRK2 genes are the most common genetic risk factors associated with Parkinson disease (PD). Both genes are associated with lysosomal and autophagic pathways, with the GBA1 gene encoding for the lysosomal enzyme, glucocerebrosidase (GCase) and the LRRK2 gene encoding for the leucine-rich repeat kinase 2 enzyme. GBA1-associated PD is characterized by earlier age at onset and more severe non-motor symptoms compared to sporadic PD. Mutations in the GBA1 gene can be stratified into severe, mild and risk variants depending on the clinical presentation of disease. Both a loss- and gain- of function hypothesis has been proposed for GBA1 variants and the functional consequences associated with each variant is often linked to mutation severity. On the other hand, LRRK2-associated PD is similar to sporadic PD, but with a more benign disease course. Mutations in the LRRK2 gene occur in several structural domains and affect phosphorylation of GTPases. Biochemical studies suggest a possible convergence of GBA1 and LRRK2 pathways, with double mutant carriers showing a milder phenotype compared to GBA1-associated PD. This review compares GBA1 and LRRK2-associated PD, and highlights possible genotype-phenotype associations for GBA1 and LRRK2 separately, based on biochemical consequences of single variants.

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Neuronopathic GBA1 L444P mutation accelerates Glucosylsphingosine levels and formation of hippocampal alpha-synuclein inclusions

Cited by 2 publications

References 59 publications

AAV delivery ofGBA1suppresses α-synuclein accumulation in Parkinson’s disease models and restores motor dysfunction in a Gaucher’s disease model

AAV delivery ofGBA1suppresses α-synuclein accumulation in Parkinson’s disease models and restores motor dysfunction in a Gaucher’s disease model

Genetic variations in GBA1 and LRRK2 genes: Biochemical and clinical consequences in Parkinson disease

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