GBA-Associated Synucleinopathies: Prime Candidates for Alpha-Synuclein Targeting Compounds

Brockmann, Kathrin

doi:10.3389/fcell.2020.562522

Cited by 10 publications

(6 citation statements)

References 63 publications

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“…The common phenotypes across the mutant DA neurons include α-Syn accumulation, mis-regulation of network activity and calcium oscillations. In addition, patient-derived and engineered PD DA neurons showed decreased activity of GCase enzyme which is consistent with previous studies suggesting DA neurons have reduced capability for clearing misfolded and aggregated proteins 9,28–31 . Together these data suggest a divergent etiology of PD pathogenesis between GBA N370S , LRRK2 G2019S and SNCA A53T DA neurons, described in Figure 8E and discussed in further detail throughout the discussion.…”

Section: Discussionsupporting

confidence: 91%

Diverging Parkinson’s Disease Pathology between patient-derivedGBA^N370S, LRRK2^G2019Sand engineeredSNCA^A53TiPSC-derived Dopaminergic Neurons

Fathi¹,

Bakshy²,

Zieghami³

et al. 2023

Preprint

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Multiple neurodegenerative disorders, including Parkinson,s disease (PD) and Alzheimer,s disease-associated dementia (ADAD), are linked with dopaminergic (DA) neuron death and a resulting reduction in dopamine levels in the brain. DA neuron degeneration and the risk of developing PD is connected to genetic mutations affiliated with lysosomal function and protein degradation. Accessible human cellular models for PD-relevant genetic mutations are needed to investigate mechanisms of DA cell death and define points of therapeutic intervention. Human induced pluripotent stem cell (iPSC)-derived midbrain DA neurons offer a developmentally and physiologically relevant in vitro model for investigating PD pathogenic mechanisms across genetic backgrounds. In this study, we generated DA neurons using iPSCs from two clinically diagnosed PD patients, one harboring an inherited GBAN370Smutation and the other a mutation in LRRK2G2019Sand compared pathophysiology against DA neurons from genetically engineered SNCAA53TiPSCs and its isogenic apparently healthy normal (AHN) iPSCs. Our results present a novel phenotype for GBAN370Sand LRRK2G2019Sderived DA neurons, showing that they produced and released significantly more dopamine compared to the AHN and SNCAA53Tmutant DA neurons. All mutant DA neurons developed deficient glucocerebrosidase (GCase) activity, increased mitochondrial stress, aberrant neuronal activity patterns, and increased α-synuclein accumulation. Together these data suggest potentially divergent origins of PD pathogenesis in GBAN370Sand LRRK2G2019SDA neurons. In addition, compound screening confirmed that GCase modulators can rescue enzyme activity and impact neural activity across all DA mutant neurons, to varying degrees. These data demonstrate unique in vitro phenotypes associated with PD and suggest a diversity of underlying mechanisms across different genetic backgrounds. Together, the cell lines used in this study present a valuable tool for new therapeutic discovery.

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Section: Discussionsupporting

confidence: 91%

Diverging Parkinson’s Disease Pathology between patient-derivedGBA^N370S, LRRK2^G2019Sand engineeredSNCA^A53TiPSC-derived Dopaminergic Neurons

Fathi¹,

Bakshy²,

Zieghami³

et al. 2023

Preprint

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“…Furthermore, changes in lipid metabolism and accumulation of glucosylceramide, its substrate, are observed [ 192 ]. Interestingly, numerous studies show GCase to interact with alpha-synuclein [ 189 , 193 ]. However, the deleterious effect of loss of Gba in alpha-synuclein expressing flies remains unclear [ 39 , 194 ].…”

Section: Lipids As Connecting Factor Between Mitochondrial Dysfuncmentioning

confidence: 99%

The Importance of Drosophila melanogaster Research to UnCover Cellular Pathways Underlying Parkinson’s Disease

Vos

Klein

2021

Cells

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Parkinson’s disease (PD) is a complex neurodegenerative disorder that is currently incurable. As a consequence of an incomplete understanding of the etiology of the disease, therapeutic strategies mainly focus on symptomatic treatment. Even though the majority of PD cases remain idiopathic (~90%), several genes have been identified to be causative for PD, facilitating the generation of animal models that are a good alternative to study disease pathways and to increase our understanding of the underlying mechanisms of PD. Drosophila melanogaster has proven to be an excellent model in these studies. In this review, we will discuss the different PD models in flies and key findings identified in flies in different affected pathways in PD. Several molecular changes have been identified, of which mitochondrial dysfunction and a defective endo-lysosomal pathway emerge to be the most relevant for PD pathogenesis. Studies in flies have significantly contributed to our knowledge of how disease genes affect and interact in these pathways enabling a better understanding of the disease etiology and providing possible therapeutic targets for the treatment of PD, some of which have already resulted in clinical trials.

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“…While contradictory at first sight, ceramide function is defined by its cellular localization and species length [ 96 ], providing a possible explanation for this discrepancy. Furthermore, mutations in GBA ( Figure 2 ) are the most common genetic risk factor for PD [ 97 , 98 ]. GBA encodes Glucocerebrosidase (GCase), which forms ceramide through the hydrolysis of glucosylceramide [ 97 , 99 ].…”

Section: Parkinson’s Diseasementioning

confidence: 99%

Neurodegenerative Disorders: Spotlight on Sphingolipids

Mandik

Vos

2021

IJMS

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Neurodegenerative diseases are incurable diseases of the nervous system that lead to a progressive loss of brain areas and neuronal subtypes, which is associated with an increase in symptoms that can be linked to the affected brain areas. The key findings that appear in many neurodegenerative diseases are deposits of proteins and the damage of mitochondria, which mainly affect energy production and mitophagy. Several causative gene mutations have been identified in various neurodegenerative diseases; however, a large proportion are considered sporadic. In the last decade, studies linking lipids, and in particular sphingolipids, to neurodegenerative diseases have shown the importance of these sphingolipids in the underlying pathogenesis. Sphingolipids are bioactive lipids consisting of a sphingoid base linked to a fatty acid and a hydrophilic head group. They are involved in various cellular processes, such as cell growth, apoptosis, and autophagy, and are an essential component of the brain. In this review, we will cover key findings that demonstrate the relevance of sphingolipids in neurodegenerative diseases and will focus on neurodegeneration with brain iron accumulation and Parkinson’s disease.

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GBA-Associated Synucleinopathies: Prime Candidates for Alpha-Synuclein Targeting Compounds

Cited by 10 publications

References 63 publications

Diverging Parkinson’s Disease Pathology between patient-derivedGBA^N370S, LRRK2^G2019Sand engineeredSNCA^A53TiPSC-derived Dopaminergic Neurons

Diverging Parkinson’s Disease Pathology between patient-derivedGBA^N370S, LRRK2^G2019Sand engineeredSNCA^A53TiPSC-derived Dopaminergic Neurons

The Importance of Drosophila melanogaster Research to UnCover Cellular Pathways Underlying Parkinson’s Disease

Neurodegenerative Disorders: Spotlight on Sphingolipids

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GBA-Associated Synucleinopathies: Prime Candidates for Alpha-Synuclein Targeting Compounds

Cited by 10 publications

References 63 publications

Diverging Parkinson’s Disease Pathology between patient-derivedGBAN370S, LRRK2G2019Sand engineeredSNCAA53TiPSC-derived Dopaminergic Neurons

Diverging Parkinson’s Disease Pathology between patient-derivedGBAN370S, LRRK2G2019Sand engineeredSNCAA53TiPSC-derived Dopaminergic Neurons

The Importance of Drosophila melanogaster Research to UnCover Cellular Pathways Underlying Parkinson’s Disease

Neurodegenerative Disorders: Spotlight on Sphingolipids

Contact Info

Product

Resources

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Diverging Parkinson’s Disease Pathology between patient-derivedGBA^N370S, LRRK2^G2019Sand engineeredSNCA^A53TiPSC-derived Dopaminergic Neurons

Diverging Parkinson’s Disease Pathology between patient-derivedGBA^N370S, LRRK2^G2019Sand engineeredSNCA^A53TiPSC-derived Dopaminergic Neurons