biostudies-literatureGuo ANIH Office of Research Infrastructure ProgramsNIH HHSMOST | National Natural Science Foundation of Chinae202402584https://www.ebi.ac.uk/biostudies/studies/S-EPMC11291935biostudies-literatureUnknown7(10)Cholesterol homeostasis in neurons is critical for synapse formation and maintenance. Neurons with impaired cholesterol uptake undergo progressive synapse loss and eventual degeneration. To investigate the molecular mechanisms of neuronal cholesterol homeostasis and its role during synapse development, we studied motor neurons of <i>Caenorhabditis elegans</i> because these neurons rely on dietary cholesterol. Combining lipidomic analysis, we discovered that NCR-1, a lysosomal cholesterol transporter, promotes cholesterol absorption and synapse development. Loss of <i>ncr-1</i> causes smaller synapses, and low cholesterol exacerbates the deficits. Moreover, NCR-1 deficiency hinders the increase in synapses under high cholesterol. Unexpectedly, NCR-2, the NCR-1 homolog, increases the use of Life science allianceDifferential roles of lysosomal cholesterol transporters in the development of <i>C. elegans</i> NMJs.PMC112919353216018731970922P40 OD010440Liu YLiang DLuo QYang YChen KXiong MWu QFei EChen FGuo AYan XYu YfalseDifferential roles of lysosomal cholesterol transporters in the development of <i>C. elegans</i> NMJs.Cholesterol homeostasis in neurons is critical for synapse formation and maintenance. Neurons with impaired cholesterol uptake undergo progressive synapse loss and eventual degeneration. To investigate the molecular mechanisms of neuronal cholesterol homeostasis and its role during synapse development, we studied motor neurons of <i>Caenorhabditis elegans</i> because these neurons rely on dietary cholesterol. Combining lipidomic analysis, we discovered that NCR-1, a lysosomal cholesterol transporter, promotes cholesterol absorption and synapse development. Loss of <i>ncr-1</i> causes smaller synapses, and low cholesterol exacerbates the deficits. Moreover, NCR-1 deficiency hinders the increase in synapses under high cholesterol. Unexpectedly, NCR-2, the NCR-1 homolog, increases the use of 2024-01-01T00:00:00Z2024 Oct2026-07-15T09:39:38.39Z2025-05-18T13:34:56.833ZS-EPMC112919353908487510.26508/lsa.202402584