Activation of ABCC1 transporter ameliorates synaptic dysregulation in Tay-Sachs disease neuron.

Tay-Sachs disease (TSD) is a congenital lysosomal storage disorder, caused by deficiency in the α-subunit of β-hexosaminidase A, leading to GM2 ganglioside accumulation in the central nervous system. Patients with TSD exhibit neural disturbances such as seizures, mental retardation; however, the molecular mechanisms behind neurological symptoms remain unclear. This study aimed to investigate altered synaptic function and explore treatment avenues for TSD. We observed the upregulation of postsynaptic receptors, abnormally elevated Ca2+ influx by neurotransmitter, and increased cell death under oxidative stress in TSD neurons. These abnormalities were associated with GM2 ganglioside accumulation. Additionally, we found that thiethylperazine, an approval drug for anti-emetics, mitigated GM2 ganglioside accumulation, potentially by activating the ATP-binding cassette subfamily C member 1 (ABCC1) transporter. This activation consequently improved the abnormal synaptic function. Our findings suggest that synaptic dysfunction is implicated in the neural disturbance in TSD, and highlight the ABCC1 transporter as a promising therapeutic target for this disease.