α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies
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 agg...
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2018
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oai:doaj.org-article:4adc82051b0144b0a3f11de190f2a0802021-12-02T11:41:15Zα-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies10.1038/s41598-018-30808-92045-2322https://doaj.org/article/4adc82051b0144b0a3f11de190f2a0802018-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-30808-9https://doaj.org/toc/2045-2322Abstract 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.Hazem AbdelkarimMichael S. MarshallGiuseppe ScesaRachael A. SmithEmily RueJeffrey MarshallVince ElackattuMonika StoskuteYazan IssaMarta SantosDuc NguyenZane HauckRichard van BreemenMaria S. CelejVadim GaponenkoErnesto R. BongarzoneNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-19 (2018) |
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EN |
| topic |
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Medicine R Science Q Hazem Abdelkarim Michael S. Marshall Giuseppe Scesa Rachael A. Smith Emily Rue Jeffrey Marshall Vince Elackattu Monika Stoskute Yazan Issa Marta Santos Duc Nguyen Zane Hauck Richard van Breemen Maria S. Celej Vadim Gaponenko Ernesto R. Bongarzone α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies |
| description |
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. |
| format |
article |
| author |
Hazem Abdelkarim Michael S. Marshall Giuseppe Scesa Rachael A. Smith Emily Rue Jeffrey Marshall Vince Elackattu Monika Stoskute Yazan Issa Marta Santos Duc Nguyen Zane Hauck Richard van Breemen Maria S. Celej Vadim Gaponenko Ernesto R. Bongarzone |
| author_facet |
Hazem Abdelkarim Michael S. Marshall Giuseppe Scesa Rachael A. Smith Emily Rue Jeffrey Marshall Vince Elackattu Monika Stoskute Yazan Issa Marta Santos Duc Nguyen Zane Hauck Richard van Breemen Maria S. Celej Vadim Gaponenko Ernesto R. Bongarzone |
| author_sort |
Hazem Abdelkarim |
| title |
α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies |
| title_short |
α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies |
| title_full |
α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies |
| title_fullStr |
α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies |
| title_full_unstemmed |
α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies |
| title_sort |
α-synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies |
| publisher |
Nature Portfolio |
| publishDate |
2018 |
| url |
https://doaj.org/article/4adc82051b0144b0a3f11de190f2a080 |
| work_keys_str_mv |
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1718395396212916224 |