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

摘要: Aggregation of α-synuclein, the hallmark α-synucleinopathies such as Parkinson’s disease, occurs in various glycosphingolipidoses. Although α-synuclein aggregation correlates with deficiencies lysosomal degradation glycosphingolipids (GSL), mechanism(s) involved this remains unclear. We previously described Krabbe’s disease (KD), a neurodegenerative glycosphingolipidosis caused by deficiency galactosyl-ceramidase (GALC) and accumulation GSL psychosine. Here, we used multi-pronged approach including genetic, biophysical biochemical techniques to determine pathogenic contribution, reversibility, molecular mechanism KD. While genetic knock-out reduces, but does not completely prevent, neurological signs mouse model KD, correction GALC prevents aggregation. show that psychosine forms hydrophilic clusters binds C-terminus through its amino group sugar moiety, suggesting promotes an open/aggregation-prone conformation α-synuclein. Dopamine carbidopa reverse structural changes mediating closed/aggregation-resistant Our results underscore therapeutic potential small molecules reduce neuronal burden α-synucleinopathies, provide mechanistic understanding