α-Synuclein interacts directly but reversibly with psychosine: implications for α-synucleinopathies

Autor: Ernesto R. Bongarzone, Marta B. Santos, Vadim Gaponenko, Giuseppe Scesa, Michael S. Marshall, Maria Soledad Celej, Richard B. van Breemen, Duc Nguyen, Jeffrey N. Marshall, Zane Hauck, Rachael A. Smith, Vince Elackattu, Monika Stoskute, Yazan Issa, Emily A. Rue, Hazem Abdelkarim
Rok vydání: 2018
Předmět:
Zdroj: Scientific Reports
CONICET Digital (CONICET)
Consejo Nacional de Investigaciones Científicas y Técnicas
instacron:CONICET
Scientific Reports, Vol 8, Iss 1, Pp 1-19 (2018)
ISSN: 2045-2322
Popis: 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. Fil: Abdelkarim, Hazem. University of Illinois; Estados Unidos Fil: Marshall, Michael S.. University of Illinois; Estados Unidos Fil: Scesa, Giuseppe. University of Illinois; Estados Unidos Fil: Smith, Rachael A.. University of Illinois; Estados Unidos Fil: Rue, Emily. University of Illinois; Estados Unidos Fil: Marshall, Jeffrey. University of Illinois; Estados Unidos Fil: Elackattu, Vince. University Of Illinois Chicago; Estados Unidos Fil: Stoskute, Monika. University Of Illinois Chicago; Estados Unidos Fil: Issa, Yazan. University Of Illinois Chicago; Estados Unidos Fil: Santos, Marta. University Of Illinois Chicago; Estados Unidos Fil: Nguyen, Duc. University Of Illinois Chicago; Estados Unidos Fil: Hauck, Zane. University Of Illinois Chicago; Estados Unidos Fil: Van Breemen, Richard B.. University Of Illinois Chicago; Estados Unidos Fil: Celej, Maria Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina Fil: Gaponenko, Vadim. University Of Illinois Chicago; Estados Unidos Fil: Bongarzone, Ernesto R.. University Of Illinois Chicago; Estados Unidos
Databáze: OpenAIRE
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