Impaired docking and recycling of synaptic vesicles in inherited lysosomal sphingolipidoses.

Abstract

Cognitive, memory, and learning impairments are common features of many lysosomal sphingolipidoses, yet the underlying synaptic mechanisms remain poorly defined. Here, we examined the impact of galactosylceramidase (GALC) deficiency on synaptic structure and function in the Twitcher (TWI) mouse model of Krabbe disease (KD). In vivo electrophysiological recording revealed significant cell autonomous reductions in paired-pulse facilitation and excitatory postsynaptic potential amplitude in hippocampal neurons of TWI mice. These functional impairments were accompanied by notable decreases in dendritic spine density, disrupted synaptic vesicle distribution, and reduced size of postsynaptic densities, affecting both excitatory and inhibitory synapses. Mechanistically, we found that psychosine, the pathological sphingolipid in KD, accumulated preferentially in presynaptic membranes and synaptic vesicles. Moreover, its higher biosynthetic rate in synaptosome fractions suggests local synthesis within the synaptic compartment. Deregulation of the SNARE protein SNAP25 and increased formation of SNARE complexes pointed to reduced vesicle docking and fusion at the presynaptic membrane. In vitro assays confirmed that psychosine disrupts synaptic vesicle cycling and SNARE-mediated fusion. Comparative analysis of other disease-associated sphingolipids-including gangliosides, sulfatides, glucosylsphingosine, globotriaosylceramide, sphingomyelin, and sphingosine-revealed distinct effects on vesicle trafficking, underscoring convergent yet lipid-specific mechanisms across inherited sphingolipidoses. Collectively, these findings identify presynaptic sphingolipid accumulation and impaired vesicle docking and fusion as shared mechanisms contributing to synaptic failure in several inherited sphingolipidoses, with potential relevance in adult-onset neurodegenerative diseases where lysosomal function is also compromised.