Details

Autor(en) / Beteiligte

• Mitroi, Daniel N
• Pereyra‐Gómez, Guadalupe
• Soto‐Huelin, Beatriz
• Senovilla, Fernando
• Kobayashi, Toshihide
• Esteban, Jose A
• Ledesma, María Dolores

Titel

NPC1 enables cholesterol mobilization during long‐term potentiation that can be restored in Niemann–Pick disease type C by CYP46A1 activation

Ist Teil von

• EMBO reports, 2019-11, Vol.20 (11), p.e48143-n/a

Ort / Verlag

England: Blackwell Publishing Ltd

Erscheinungsjahr

2019

Link zum Volltext

Quelle

Wiley Blackwell Single Titles

Beschreibungen/Notizen

• NPC is a neurodegenerative disorder characterized by cholesterol accumulation in endolysosomal compartments. It is caused by mutations in the gene encoding NPC1, an endolysosomal protein mediating intracellular cholesterol trafficking. Cognitive and psychiatric alterations are hallmarks in NPC patients pointing to synaptic defects. However, the role of NPC1 in synapses has not been explored. We show that NPC1 is present in the postsynaptic compartment and is locally translated during LTP. A mutation in a region of the NPC1 gene commonly altered in NPC patients reduces NPC1 levels at synapses due to enhanced NPC1 protein degradation. This leads to shorter postsynaptic densities, increased synaptic cholesterol and impaired LTP in NPC1nmf164 mice with cognitive deficits. NPC1 mediates cholesterol mobilization and enables surface delivery of CYP46A1 and GluA1 receptors necessary for LTP, which is defective in NPC1nmf164 mice. Pharmacological activation of CYP46A1 normalizes synaptic levels of cholesterol, LTP and cognitive abilities, and extends life span of NPC1nmf164 mice. Our results unveil NPC1 as a regulator of cholesterol dynamics in synapses contributing to synaptic plasticity, and provide a potential therapeutic strategy for NPC patients. Synopsis NPC1 mediates cholesterol mobilization and CYP46A1 and AMPA receptor surface delivery during LTP facilitating learning and memory. Mutations in NPC1 leading to the protein degradation impair this role, which can be rescued by the CYP46A1 activator Efavirenz in NPC1 mutant mice, opening therapeutic perspectives for NPC patients.. NPC1 is present in synapses and mediates cholesterol mobilization during LTP that is necessary for CYP46A1 and AMPA receptor surface delivery. Activation of CYP46A1 with the medicine Efavirenz reduces excess cholesterol in synapses and restores AMPA receptor surface delivery and LTP when NPC1 is deficient. Oral treatment with Efavirenz prevents brain cholesterol accumulation, cognitive alterations and extends life span in NPC1 mutant mice. NPC1 mediates cholesterol mobilization and CYP46A1 and AMPA receptor surface delivery during long‐term potentiation facilitating learning and memory. Treatment with the CYP46A1 activator Efavirenz can restore these processes in NPC1 mutant mice.