Seed-competent α-synuclein pathology in metachromatic leukodystrophy: the expanding spectrum of α-synucleinopathy in sphingolipidoses

Metachromatic leukodystrophy (MLD) is a rare - typically paediatric - sphingolipid storage disorder resulting from bi-allelic pathogenic variants in the ARSA gene, encoding the lysosomal arylsulphatase A (ASA). Heterozygous variants in ARSA are associated with risk of Lewy body diseases (LBD), a group of age-associated neurodegenerative disorders characterised by the accumulation of the protein α-synuclein; however, no study has yet determined whether α-synuclein with putative pathological features is observed in MLD brain tissue. We examined post-mortem brain tissue from MLD cases (N=5, age 2-33) compared to matched control cases using histological approaches and α-synuclein seeding amplification assay (SAA). Juvenile-onset MLD cases exhibited granular α-synuclein deposits in neurons of regions prone to neuronal pathology in MLD, and seed-competent conformers that generated atypical short, twisted fibrils on SAA. In contrast, infantile-onset MLD cases gave only variably positive reactions on SAA. In summary, this study suggests MLD cases manifest α-synuclein pathology reminiscent of that observed in LBD, even in juvenile populations, further expanding the spectrum of sphingolipid storage disorders associated with the aggregation of α-synuclein. These findings have important implications for understanding the disease process of both LBD and MLD, potentially highlighting novel pathways for therapeutic interventions in both conditions.