Altered expression of genes involved in ganglioside biosynthesis in substantia nigra neurons in Parkinson’s disease

Schneider, Jay S.

doi:10.1371/journal.pone.0199189

Cited by 62 publications

(57 citation statements)

References 40 publications

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“…In other experimental models of Parkinson's disease, GM1 has been shown to be successful when injected directly into the cerebral ventricles. Overall, these results indicate that when the ganglioside reaches the neuronal membranes, it is able to reduce and counteract the progression of the disease [7,130].…”

Section: Administration Of Gm1 and Modified Gm1 To B4galnt1 −/+ Micementioning

confidence: 68%

“…These findings suggest a ganglioside systemic deficiency that would correlate with the systemic symptoms of sporadic Parkinson's disease. The decreasing expression of mentioned genes and the resulting decrease in brain of a-series gangliosides (GM1, GD1a) presume impaired composition and disorganization of neuronal plasma membrane, which may increase the neurons vulnerability to degeneration [130].…”

Section: Gm1 and Parkinson's Diseasementioning

confidence: 99%

“…Among other, two functions have commanded special attention regarding Parkinson's disease: neuroprotective signaling via neurotrophic receptors and α-synuclein interaction. 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].…”

Section: Gm1 and Parkinson's Diseasementioning

confidence: 99%

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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: Administration Of Gm1 and Modified Gm1 To B4galnt1 −/+ Micementioning

confidence: 68%

Section: Gm1 and Parkinson's Diseasementioning

confidence: 99%

Section: Gm1 and Parkinson's Diseasementioning

confidence: 99%

See 1 more Smart Citation

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

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“…In conclusion, our data suggest that microglial gangliosides play an important role in the regulation of crucial microglia activities -including response to inflammatory stimuli, chemotaxis and phagocytosis -that might be compromised as a result of decreased ganglioside synthesis in neurodegenerative disorders such as PD [34,113] and HD [32,33]. Our studies provide important insights into the therapeutic role of GM1 in neurodegenerative disease and demonstrate that the ganglioside can target inflammatory microglia in addition to neurons.…”

Section: Discussionmentioning

confidence: 66%

Anti-inflammatory role of GM1 and modulatory effects of gangliosides on microglia functions

Galleguillos

Qian

Steinberg

et al. 2020

Preprint

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Gangliosides are sialic acid-containing glycosphingolipids highly enriched in the brain. Located mainly at the plasma membrane, gangliosides play important roles in signaling and cell-to-cell communication. Lack of gangliosides causes severe early onset neurodegenerative disorders, while more subtle deficits have been reported in Parkinson's disease and in Huntington's disease, two misfolded protein diseases with a neuroinflammatory component. On the other hand, administration of ganglioside GM1 provides neuroprotection in both diseases and in several other models of neuronal insult. While most studies have focused on the role of endogenous gangliosides and the effects of exogenously administered GM1 in neurons, their contribution to microglia functions that are affected in neurodegenerative conditions is largely unexplored.Microglia are the immune cells of the brain and play important homeostatic functions in health and disease. In this study, we show that administration of exogenous GM1 exerts a potent antiinflammatory effect on microglia activated with LPS, IL-1β or upon phagocytosis of latex beads.These effects are partially reproduced by L-t-PDMP, a compound that stimulates the activity of the ganglioside biosynthetic pathway, while inhibition of ganglioside synthesis with GENZ-123346 increases microglial transcriptional response to LPS. We further show that administration of GM1 increases the uptake of apoptotic bodies and latex beads by microglia, as well as microglia migration and chemotaxis in response to ATP. On the contrary, decreasing microglial ganglioside levels results in a partial impairment in both microglial activities. Finally, increasing cellular ganglioside levels results in decreased expression and secretion of microglial brain derived neurotrophic factor (BDNF). Altogether, our data suggest that gangliosides are important modulators of microglia functions that are crucial to healthy brain homeostasis, and reveal that administration of ganglioside GM1 exerts an important anti-inflammatory activity that could be exploited therapeutically.

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“…Further, cleavage of extracellular N-linked glycans, but not other carbohydrates, reduced α-synuclein cellular internalization, and a neuronal glycoprotein neurexin-1β can mediate glycan-dependent α-synuclein uptake [100]. GM1 is expressed in an age-dependent manner, and significant GM1 deficiencies have been observed in nigral dopaminergic neurons from PD patients [101]. Importantly, GM1-deficient animals display Parkinson-like symptoms that were alleviated by administration of LIGA-20 (a blood-brain barrier-permeable GM1 analogue) [102] Thus, GM1 ganglioside deficiency is believed to be one of the triggers of PD, suggesting that GM1 can be a potential therapeutic target for PD treatment.…”

Section: Glycans In Parkinson's Diseasementioning

confidence: 99%

Glycan Mimetics from Natural Products: New Therapeutic Opportunities for Neurodegenerative Disease

et al. 2019

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Neurodegenerative diseases (NDs) affect millions of people worldwide. Characterized by the functional loss and death of neurons, NDs lead to symptoms (dementia and seizures) that affect the daily lives of patients. In spite of extensive research into NDs, the number of approved drugs for their treatment remains limited. There is therefore an urgent need to develop new approaches for the prevention and treatment of NDs. Glycans (carbohydrate chains) are ubiquitous, abundant, and structural complex natural biopolymers. Glycans often covalently attach to proteins and lipids to regulate cellular recognition, adhesion, and signaling. The importance of glycans in both the developing and mature nervous system is well characterized. Moreover, glycan dysregulation has been observed in NDs such as Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). Therefore, glycans are promising but underexploited therapeutic targets. In this review, we summarize the current understanding of glycans in NDs. We also discuss a number of natural products that functionally mimic glycans to protect neurons, which therefore represent promising new therapeutic approaches for patients with NDs.

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Altered expression of genes involved in ganglioside biosynthesis in substantia nigra neurons in Parkinson’s disease

Cited by 62 publications

References 40 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

Anti-inflammatory role of GM1 and modulatory effects of gangliosides on microglia functions

Glycan Mimetics from Natural Products: New Therapeutic Opportunities for Neurodegenerative Disease

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