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

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

Scientific Reports

Nature Publishing Group

Año: 2018 vol. 8

ggregation 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 aggregati