Authors:

Riya Voruganti

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Krabbe Disease (KD) is a fatal lysosomal disorder caused by deficiency of galactosylceramidase (GALC), leading to accumulation of the cytotoxic sphingolipid psychosine. Although KD is characterized as a demyelinating leukodystrophy, patients also exhibit significant cognitive and behavioral impairments, suggesting neuronal dysfunction. However, the synaptic mechanisms underlying these features remain poorly defined. In this study, we investigated how galactosylceramidase (GALC) deficiency affects synaptic structure and function using the Twitcher (TWI) mouse model of KD. In vivo electrophysiological recordings demonstrated significant reductions in paired-pulse facilitation and excitatory postsynaptic potential amplitudes in hippocampal neurons from TWI mice. Additionally, decreased dendritic spine density, abnormal synaptic vesicle organization, and reduced postsynaptic density size at both excitatory and inhibitory synapses were found. Mechanistically, we observed that psychosine accumulated mainly within presynaptic membranes and synaptic vesicles. Its elevated biosynthetic rate in TWI synaptosomal fractions further suggests local production within synaptic compartments. Dysregulation of the SNARE protein SNAP25, together with enhanced SNARE complex formation, indicated impaired vesicle docking and fusion at presynaptic membranes. Consistent with these findings, in vitro assays confirmed that psychosine disrupts synaptic vesicle cycling and SNARE-dependent membrane fusion. Collectively, our findings identify presynaptic psychosine accumulation and defective vesicle docking and fusion as drivers of synaptic dysfunction in KD. This work reframes KD as not only a demyelinating disorder but also a disorder with synaptic pathology, providing mechanistic insight into the neuronal dysfunction underlying cognitive impairment in affected patients. This research was funded by grants from NIH-NINDS (R01 NS065808, RO1NS127403), and the European Leukodystrophy Association to E.R.B, and from the Rosenau Family Research Foundation to D.Z and E.R.B. POSS OSSSEHOOSS SS SSH OOS S SHES OOS SEC SSE SSO ESSE SOOO FVPIIFIFIFFIDHIODIDIDFIHODIDIDIDIDIDHDIDIIIIHOHHDHIIIBO

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University of Illinois Chicago

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Co-authors:

Riya Voruganti