GM1 Ganglioside Modifies α-Synuclein Toxicity and is Neuroprotective in a Rat α-Synuclein Model of Parkinson’s Disease

Schneider, Jay S.; Aras, Radha; Williams, Courtney K.; Koprich, James B.; Brotchie, Jonathan M.; Singh, Vikrant

doi:10.1038/s41598-019-42847-x

Cited by 55 publications

(50 citation statements)

References 44 publications

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“…It has been hypothesized that the reduced level of plasma membrane GM1 in Parkinon's neurons can trigger the neurodegenerative process by a failure in neurotrophic signaling (e.g., BDNF/GDNF/NGF) together with a reduction of clearance promoting the α-synuclein accumulation [7,9,104,106,129,130]. Along with this, recent studies strongly demonstrated the specific binding of tetrameric α-synuclein to GM1 which promotes its α-helical conformation against the beta-sheet-rich state of α-synuclein that has been associated with its pathological aggregation in Parkinson's disease [132][133][134]. Additionally, Schneider recently reported that GM1 modifies the alpha-synuclein toxicity and is neuroprotective in a rat α -synuclein model of Parkinson's disease reducing the size of α -synuclein positive aggregates [123].…”

Section: Gm1 and Parkinson's Diseasementioning

confidence: 99%

GM1 Ganglioside Is A Key Factor in Maintaining the Mammalian Neuronal Functions Avoiding Neurodegeneration

Chiricozzi

Lunghi

Biase

et al. 2020

IJMS

140

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Many species of ganglioside GM1, differing for the sialic acid and ceramide content, have been characterized and their physico-chemical properties have been studied in detail since 1963. Scientists were immediately attracted to the GM1 molecule and have carried on an ever-increasing number of studies to understand its binding properties and its neurotrophic and neuroprotective role. GM1 displays a well balanced amphiphilic behavior that allows to establish strong both hydrophobic and hydrophilic interactions. The peculiar structure of GM1 reduces the fluidity of the plasma membrane which implies a retention and enrichment of the ganglioside in specific membrane domains called lipid rafts. The dynamism of the GM1 oligosaccharide head allows it to assume different conformations and, in this way, to interact through hydrogen or ionic bonds with a wide range of membrane receptors as well as with extracellular ligands. After more than 60 years of studies, it is a milestone that GM1 is one of the main actors in determining the neuronal functions that allows humans to have an intellectual life. The progressive reduction of its biosynthesis along the lifespan is being considered as one of the causes underlying neuronal loss in aged people and severe neuronal decline in neurodegenerative diseases. In this review, we report on the main knowledge on ganglioside GM1, with an emphasis on the recent discoveries about its bioactive component.

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Section: Gm1 and Parkinson's Diseasementioning

confidence: 99%

GM1 Ganglioside Is A Key Factor in Maintaining the Mammalian Neuronal Functions Avoiding Neurodegeneration

Chiricozzi

Lunghi

Biase

et al. 2020

IJMS

140

View full text Add to dashboard Cite

show abstract

“…It was found that all major brain gangliosides were significantly decreased in male PD patients compared to healthy controls ( Seyfried et al, 2018 ). Pilot studies further showed that treating PD Patients with GM1 ganglioside could provide a disease modifying therapy and that GM1 administration reduced the size of α-syn aggregates in a rodent AAV-α-syn overexpression model ( Schneider et al, 2013 , 2015 , 2019 ). However, research of human brain lipidomics of different brain areas or cell types during aging in health and disease is limited.…”

Section: Lipid Binding Modulates Initial α-Synuclein Aggregationmentioning

confidence: 99%

The Role of Lipids in the Initiation of α-Synuclein Misfolding

Kiechle

Grozdanov

Danzer

2020

Front. Cell Dev. Biol.

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The aggregation of α-synuclein (α-syn) is inseparably connected to Parkinson's disease (PD). It is now well-established that certain forms of α-syn aggregates, oligomers and fibrils, can exert neurotoxicity in synucleinopathies. With the exception of rare familial forms, the vast majority of PD cases are idiopathic. Understanding the earliest molecular mechanisms that cause initial α-syn misfolding could help to explain why PD affects only some individuals and others not. Factors that chaperone the transition of α-syn's physiological to pathological function are of particular interest, since they offer opportunities for intervention. The relationship between α-syn and lipids represents one of those factors. Membrane interaction is crucial for normal cellular function, but lipids also induce the aggregation of α-syn, causing cell toxicity. Also, disease-causing or risk-factor mutations in genes related to lipid metabolism like PLA2G6, SCARB2 or GBA1 highlight the close connection between PD and lipids. Despite the clear link, the ambivalent interaction has not been studied sufficiently so far. In this review, we address how α-syn interacts with lipids and how they can act as key factor for orchestrating toxic conversion of α-syn. Furthermore, we will discuss a scenario in which initial α-syn aggregation is determined by shifts in lipid/α-syn ratio as well as by dyshomeostasis of membrane bound/unbound state of α-syn.

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“…In neurodegenerative diseases such as Parkinson's and Alzheimer's diseases, despite the great preclinical successes [18,19,[68][69][70][71], GM1 did not reach a sufficient amount in the brain target site to perform its reparative functions. Probably the reason is that these clinical trials included peripheral administration of the ganglioside, which inefficiently permeates through the BBB.…”

Section: Discussionmentioning

confidence: 99%

GM1 Oligosaccharide Crosses the Human Blood–Brain Barrier In Vitro by a Paracellular Route

Biase

Lunghi

Maggioni

et al. 2020

IJMS

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Ganglioside GM1 (GM1) has been reported to functionally recover degenerated nervous system in vitro and in vivo, but the possibility to translate GM1 s potential in clinical settings is counteracted by its low ability to overcome the blood-brain barrier (BBB) due to its amphiphilic nature. Interestingly, the soluble and hydrophilic GM1-oligosaccharide (OligoGM1) is able to punctually replace GM1 neurotrophic functions alone, both in vitro and in vivo. In order to take advantage of OligoGM1 properties, which overcome GM1 s pharmacological limitations, here we characterize the OligoGM1 brain transport by using a human in vitro BBB model. OligoGM1 showed a 20-fold higher crossing rate than GM1 and time-concentration-dependent transport. Additionally, OligoGM1 crossed the barrier at 4 • C and in inverse transport experiments, allowing consideration of the passive paracellular route. This was confirmed by the exclusion of a direct interaction with the active ATP-binding cassette (ABC) transporters using the "pump out" system. Finally, after barrier crossing, OligoGM1 remained intact and able to induce Neuro2a cell neuritogenesis by activating the TrkA pathway. Importantly, these in vitro data demonstrated that OligoGM1, lacking the hydrophobic ceramide, can advantageously cross the BBB in comparison with GM1, while maintaining its neuroproperties. This study has improved the knowledge about OligoGM1 s pharmacological potential, offering a tangible therapeutic strategy.However, transferring the GM1 neuronal potential from the preclinical models to the clinic depends on its ability to reach the brain structures when administered peripherally. This last aspect is actually severely limited by GM1 s amphiphilicity, which hampers the passage across the blood-brain barrier (BBB) [2,7,8]. This barrier is located at the brain microvessel level and strongly restricts the entry of cells and xenobiotics into the CNS. The BBB anatomical support is the specialized brain endothelial cells of these vessels. These cells do not show any fenestrations and are specifically characterized by the presence of tight junctions (TJ), composed of junctional proteins and TJ-associated proteins. Additionally, these cells express several proteins belonging to the ATP-binding cassette (ABC) transporters family, which act as efflux pumps and play an important role by limiting BBB crossing of several drugs and biological molecules [9,10]. The major efflux pumps expressed at the BBB are P-glycoprotein (P-gp, aka ABCB1), breast cancer resistance protein (BCRP, aka ABCG2), and the multidrug-resistance-associated proteins (MRPs, aka ABCCs).Importantly, the fate of peripherally administered GM1 observed in the rodent models has not been determined in humans, as often the two species display different BBB permeability rates for the same molecule [7,8]. One of the possible explanations for these discrepancies is the species difference recently reported between rodents and human for the expression of several receptors and transporters expressed in the BBB, in...

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GM1 Ganglioside Modifies α-Synuclein Toxicity and is Neuroprotective in a Rat α-Synuclein Model of Parkinson’s Disease

Cited by 55 publications

References 44 publications

GM1 Ganglioside Is A Key Factor in Maintaining the Mammalian Neuronal Functions Avoiding Neurodegeneration

GM1 Ganglioside Is A Key Factor in Maintaining the Mammalian Neuronal Functions Avoiding Neurodegeneration

The Role of Lipids in the Initiation of α-Synuclein Misfolding

GM1 Oligosaccharide Crosses the Human Blood–Brain Barrier In Vitro by a Paracellular Route

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