Neuronopathic Gaucher disease is caused by mutations in GBA1 that encodes lysosomal acid β-glucosidase (GCase) that has glucosylceramide (GC) and its un-acylated form, glucosylsphingosine (GS) as substrates. Conduritol B epoxide (CBE) is an irreversible covalently bound GCase inhibitor. Differentiated N2a cells treated with CBE resulted in significant GC and GS accumulation in CBE-N2a cells, thereby creating a nGD model. CBE-N2a cells had higher calcium levels than in N2a cells without caffeine at baseline and higher cytosolic calcium levels compared to N2a cells. CBE-N2a cells showed a significant reduction in OCR (oxygen consumption rate) as evidenced by rate of ATP production, basal respiration and maximal respiration, compared to N2a cells, indicating reduced mitochondrial function in this nGD cell model[2]. In vivo, long-term daily CBE treatment (100 mg/kg) of 4L mice led to hind limb paralysis and small amounts of α-synuclein accumulation in the olfactory bulb and brainstem[3].
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