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

GAPONENKO, VADIM; HAUCK, ZANE; ISSA, YAZAN; MARSHALL, JEFFREY; SCESA, GIUSEPPE; BONGARZONE, ERNESTO R.; VAN BREEMEN, RICHARD; CELEJ, MARIA S.; SANTOS, MARTA; NGUYEN, DUC; ELACKATTU, VINCE; STOSKUTE, MONIKA; SMITH, RACHAEL A.; RUE, EMILY; ABDELKARIM, HAZEM; MARSHALL, MICHAEL S.

Scientific Reports

Nature Publishing Group

Año: 2018 vol. 8

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.