Live cell in situ lysosomal GCase activity correlates to alpha-synuclein levels in human differentiated neurons with LRRK2 and GBA1 mutations

Labrador-Garrido, Adahir; Zhong, Siying; Hughes, Laura; Keshiya, Shikara; Kim, Woojin S.; Halliday, Glenda M.; Dzamko, Nicolas

doi:10.3389/fncel.2023.1229213

Cited by 4 publications

(2 citation statements)

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“…The mutant enzyme is unable to degrade its substrate, lysosphingolipids, which accumulate in the lysosome and lead to lysosomal dysfunction. As a result, the toxic forms of α-synuclein protein are accumulated [ 23 ]. The presence of α-synuclein protein has been observed in both neurons and astrocytes [ 8 , 24 ].…”

Section: Discussionmentioning

confidence: 99%

IPSC-Derived Astrocytes Contribute to In Vitro Modeling of Parkinson’s Disease Caused by the GBA1 N370S Mutation

Yarkova,

Grigor’eva,

Medvedev

et al. 2023

IJMS

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Parkinson’s disease (PD) is a neurodegenerative disorder that ranks second in prevalence after Alzheimer’s disease. The number of PD diagnoses increases annually. Nevertheless, modern PD treatments merely mitigate symptoms rather than preventing neurodegeneration progression. The creation of an appropriate model to thoroughly study the mechanisms of PD pathogenesis remains a current challenge in biomedicine. Recently, there has been an increase in data regarding the involvement of not only dopaminergic neurons of the substantia nigra but also astrocytes in the pathogenesis of PD. Cell models based on induced pluripotent stem cells (iPSCs) and their differentiated derivatives are a useful tool for studying the contribution and interaction of these two cell types in PD. Here, we generated two iPSC lines, ICGi034-B and ICGi034-C, by reprogramming peripheral blood mononuclear cells of a patient with a heterozygous mutation c.1226A>G (p.N370S) in the GBA1 gene by non-integrating episomal vectors encoding OCT4, KLF4, L-MYC, SOX2, LIN28, and mp53DD. The iPSC lines demonstrate the expression of pluripotency markers and are capable of differentiating into three germ layers. We differentiated the ICGi034-B and ICGi034-C iPSC lines into astrocytes. This resulting cell model can be used to study the involvement of astrocytes in the pathogenesis of GBA-associated PD.

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Section: Discussionmentioning

confidence: 99%

IPSC-Derived Astrocytes Contribute to In Vitro Modeling of Parkinson’s Disease Caused by the GBA1 N370S Mutation

Yarkova,

Grigor’eva,

Medvedev

et al. 2023

IJMS

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“…The link between GCase function and α-synuclein pathology has been proposed from post-mortem tissue analysis showing an inverse correlation of low GCase and high αsynuclein pathology [14,80,81]. Several in vitro studies also show that this inverse correlation and that GCase activity is inhibited by α-synuclein fibrils [82][83][84]. To understand if there is a direct interaction between GCase activity and α-synuclein pathology, GCase was inhibited by shRNA knockdown or CBE treatment and α-synuclein aggregation in response to α-synuclein PFFs treatment in primary neuron cells was evaluated, showing that GCase inhibition increased phospho-α-synuclein aggregation and/or release of α-synuclein fibrils [70,71,82].…”

Section: Fig 6 Efficacy Of Aav5-gba1 On Gcase Activity Glcsph Accumul...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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Study protocol of the GRoningen early-PD Ambroxol treatment (GREAT) trial: a randomized, double-blind, placebo-controlled, single center trial with ambroxol in Parkinson patients with a GBA mutation

Siemeling,

Slingerland,

van der Zee

et al. 2024

BMC Neurol

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Background To date, no disease modifying therapies are available for Parkinson’s disease (PD). Since PD is the second most prevalent neurodegenerative disorder, there is a high demand for such therapies. Both environmental and genetic risk factors play an important role in the etiology and progression of PD. The most common genetic risk factor for PD is a mutation in the GBA1(GBA)-gene, encoding the lysosomal enzyme glucocerebrosidase (GCase). The mucolytic ambroxol is a repurposed drug, which has shown the property to upregulate GCase activity in-vitro and in-vivo. Ambroxol therefore has the potency to become a disease modifying therapy in PD, which was the reason to design this randomized controlled trial with ambroxol in PD patients. Methods This trial is a single-center, double-blind, randomized, placebo-controlled study, including 80 PD patients with a GBA mutation, receiving either ambroxol 1800 mg/day or placebo for 48 weeks. The primary outcome measure is the Unified Parkinson’s Disease Rating Scale motor subscore (part III) of the Movement Disorder Society (MDS-UPDRSIII) in the practically defined off-state at 60 weeks (after a 12-week washout period). Secondary outcomes include a 3,4-dihydroxy-6-18F-fluoro-I-phenylalanine ([18F]FDOPA) PET-scan of the brain, Magnetic Resonance Imaging (with resting state f-MRI and Diffusion Tensor Imaging), GCase activity, both intra- and extracellularly, sphingolipid profiles in plasma, Montreal Cognitive Assessment (MoCA), quality of life (QoL) measured by the Parkinson’s Disease Questionnaire (PDQ-39) and the Non-Motor Symptom Scale (NMSS) questionnaire. Discussion Ambroxol up to 1200 mg/day has shown effects on human cerebrospinal fluid endpoints, which supports at least passage of the blood-brain-barrier. The dose titration in this trial up to 1800 mg/day will reveal if this dose level is safe and also effective in modifying the course of the disease. Trial registration NCT05830396. Registration date: March 20, 2023.

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Live cell in situ lysosomal GCase activity correlates to alpha-synuclein levels in human differentiated neurons with LRRK2 and GBA1 mutations

Cited by 4 publications

References 44 publications

IPSC-Derived Astrocytes Contribute to In Vitro Modeling of Parkinson’s Disease Caused by the GBA1 N370S Mutation

IPSC-Derived Astrocytes Contribute to In Vitro Modeling of Parkinson’s Disease Caused by the GBA1 N370S Mutation

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

Study protocol of the GRoningen early-PD Ambroxol treatment (GREAT) trial: a randomized, double-blind, placebo-controlled, single center trial with ambroxol in Parkinson patients with a GBA mutation

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