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.
Highlights
Aggregation of α-synuclein, the hallmark of α-synucleinopathies such as Parkinson’s disease, occurs in various glycosphingolipidoses
The common feature of synucleinopathies is the formation of insoluble α-synuclein aggregates in brain neurons, suggesting that different mechanisms may converge to aggregate the protein2,3. α-Synuclein is a 140-amino acid protein encoded by the SNCA gene[4,5], and encompasses three distinct regions: an amphipathic NH2-terminal region that adopts an α-helical structure upon membrane binding; a non-amyloid-β component (NAC) region involved in protein aggregation; and a highly acidic COOH-terminal region that masks the NAC region and reduces α-synuclein aggregation[4,6]
We recently showed that the deficiency of lysosomal GALC activity in Krabbe’s disease (KD)
Summary
Aggregation of α-synuclein, the hallmark of α-synucleinopathies such as Parkinson’s disease, occurs in various glycosphingolipidoses. 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. Α-Synuclein is an amyloidogenic protein involved in synucleinopathies, such as Parkinson’s disease (PD), Lewy body dementia, and several lysosomal storage diseases (LSD), including Gaucher’s disease and Krabbe’s disease (KD)[1] Despite their distinct etiology, the common feature of synucleinopathies is the formation of insoluble α-synuclein aggregates in brain neurons, suggesting that different mechanisms may converge to aggregate the protein. We find that psychosine facilitates α-synuclein aggregation via interaction between the sphingosine amino group with the negatively charged carboxy terminus of α-synuclein and the formation of galactosyl hydrophilic clusters This interaction promotes the exposure of the NAC domain, leading to aggregation. Dopamine and carbidopa, currently used in PD treatment regimens, counter the conformational changes induced by psychosine and significantly reduce the formation of protein aggregates
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