ArticleScientific reports2018
α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies.
Article in Scientific reports, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 40 citations in OpenAlex.
- Sphingolipidoses: expanding the spectrum of α-synucleinopathies.Journal of neural transmission (Vienna, Austria : 1996) · 2026Review
- Impaired docking and recycling of synaptic vesicles in inherited lysosomal sphingolipidoses.Cell communication and signaling : CCS · 2025Article
- Broken Balance: Emerging Cross-Talk Between Proteostasis and Lipostasis in Neurodegenerative Diseases.Cells · 2025Review
- High Prevalence of GALC Gene Variants in Adults With Neurodegenerative Conditions.European journal of neurology · 2025Article
- Distinct sets of lysosomal genes define synucleinopathy and tauopathy.BMB reports · 2023Article
- Neuronal Ganglioside and Glycosphingolipid (GSL) Metabolism and Disease : Cascades of Secondary Metabolic Errors Can Generate Complex Pathologies (in LSDs).Advances in neurobiology · 2023Article
- Neurodegenerative Disorder Risk in Krabbe Disease Carriers.International journal of molecular sciences · 2022Article
- Prion-like α-synuclein pathology in the brain of infants with Krabbe disease.Brain : a journal of neurology · 2022Article
- Fatty acid-binding protein 7 triggers α-synuclein oligomerization in glial cells and oligodendrocytes associated with oxidative stress.Acta pharmacologica Sinica · 2022Article
- Glycosphingolipid metabolism and its role in ageing and Parkinson's disease.Glycoconjugate journal · 2022Review
- Chronic lithium administration in a mouse model for Krabbe disease.JIMD reports · 2022Article
- Insights into Lewy body disease from rare neurometabolic disorders.Journal of neural transmission (Vienna, Austria : 1996) · 2021Review
- Impact of Gba2 on neuronopathic Gaucher's disease and α-synuclein accumulation in medaka (Oryzias latipes).Molecular brain · 2021Article
- Krabbe disease: New hope for an old disease.Neuroscience letters · 2021Review
- Lipids, lysosomes and mitochondria: insights into Lewy body formation from rare monogenic disorders.Acta neuropathologica · 2021Review
- Synaptic Function and Dysfunction in Lysosomal Storage Diseases.Frontiers in cellular neuroscience · 2021Article
- Krabbe Disease: Prospects of Finding a Cure Using AAV Gene Therapy.Frontiers in medicine · 2021Review
- Deregulation of signalling in genetic conditions affecting the lysosomal metabolism of cholesterol and galactosyl-sphingolipids.Neurobiology of disease · 2020Review
- Alpha-Synuclein in Alcohol Use Disorder, Connections with Parkinson's Disease and Potential Therapeutic Role of 5' Untranslated Region-Directed Small Molecules.Biomolecules · 2020Review
- α-synuclein promotes progression of Parkinson's disease by upregulating autophagy signaling pathway to activate NLRP3 inflammasome.Experimental and therapeutic medicine · 2020Article
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Authors and funding
16 authors at 3 institutions in 2 countries.
Funding
Abstract
Aggregation of α-synuclein, the hallmark of α-synucleinopathies such as Parkinson's disease, occurs in various glycosphingolipidoses. Although α-synuclein aggregation correlates with deficiencies in the lysosomal degradation of glycosphingolipids (GSL), the mechanism(s) involved in this aggregation remains unclear. We previously described the aggregation of α-synuclein in Krabbe's disease (KD), a neurodegenerative glycosphingolipidosis caused by lysosomal deficiency of galactosyl-ceramidase (GALC) and the accumulation of the GSL psychosine. Here, we used a multi-pronged approach including genetic, biophysical and biochemical techniques to determine the pathogenic contribution, reversibility, and molecular mechanism of aggregation of α-synuclein in KD. While genetic knock-out of α-synuclein reduces, but does not completely prevent, neurological signs in a mouse model of KD, genetic correction of GALC deficiency completely prevents α-synuclein aggregation. We show that psychosine forms hydrophilic clusters and binds the C-terminus of α-synuclein through its amino group and sugar moiety, suggesting that psychosine promotes an open/aggregation-prone conformation of α-synuclein. Dopamine and carbidopa reverse the structural changes of psychosine by mediating a closed/aggregation-resistant conformation of α-synuclein. Our results underscore the therapeutic potential of lysosomal correction and small molecules to reduce neuronal burden in α-synucleinopathies, and provide a mechanistic understanding of α-synuclein aggregation in glycosphingolipidoses.
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