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核心技术专利：CN118964589B侵权必究
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NPC1 依赖性 K2.1-Ca1.2 纳米区改变导致尼曼-匹克 C 型疾病模型中的神经元死亡。

NPC1-dependent alterations in K2.1-Ca1.2 nanodomains drive neuronal death in models of Niemann-Pick Type C disease.

机构信息

Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, CA, USA.

Department of Psychiatry & Behavioral Sciences, School of Medicine, University of California, Davis, CA, USA.

出版信息

Nat Commun. 2023 Jul 28;14(1):4553. doi: 10.1038/s41467-023-39937-w.

DOI:10.1038/s41467-023-39937-w
PMID:37507375
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10382591/
Abstract

Lysosomes communicate through cholesterol transfer at endoplasmic reticulum (ER) contact sites. At these sites, the Niemann Pick C1 cholesterol transporter (NPC1) facilitates the removal of cholesterol from lysosomes, which is then transferred to the ER for distribution to other cell membranes. Mutations in NPC1 result in cholesterol buildup within lysosomes, leading to Niemann-Pick Type C (NPC) disease, a progressive and fatal neurodegenerative disorder. The molecular mechanisms connecting NPC1 loss to NPC-associated neuropathology remain unknown. Here we show both in vitro and in an animal model of NPC disease that the loss of NPC1 function alters the distribution and activity of voltage-gated calcium channels (Ca). Underlying alterations in calcium channel localization and function are K2.1 channels whose interactions drive calcium channel clustering to enhance calcium entry and fuel neurotoxic elevations in mitochondrial calcium. Targeted disruption of K2-Ca interactions rescues aberrant Ca1.2 clustering, elevated mitochondrial calcium, and neurotoxicity in vitro. Our findings provide evidence that NPC is a nanostructural ion channel clustering disease, characterized by altered distribution and activity of ion channels at membrane contacts, which contribute to neurodegeneration.

摘要

溶酶体通过内质网 (ER) 接触点的胆固醇转移进行通讯。在这些位点上，尼曼-匹克 C1 胆固醇转运蛋白 (NPC1) 促进胆固醇从溶酶体中去除，然后将胆固醇转移到内质网，以便分配到其他细胞膜。NPC1 的突变导致溶酶体中胆固醇堆积，导致尼曼-匹克 C 型 (NPC) 疾病，这是一种进行性和致命的神经退行性疾病。NPC1 缺失与 NPC 相关神经病理学之间的分子机制仍然未知。在这里，我们通过体外和 NPC 疾病的动物模型显示，NPC1 功能的丧失改变了电压门控钙通道 (Ca) 的分布和活性。钙通道定位和功能的潜在改变是 K2.1 通道，其相互作用驱动钙通道聚集，以增强钙内流并为线粒体钙的神经毒性升高提供燃料。靶向破坏 K2-Ca 相互作用可挽救体外异常的 Ca1.2 聚集、线粒体钙升高和神经毒性。我们的发现提供了证据表明 NPC 是一种纳米结构的离子通道聚集疾病，其特征是膜接触处的离子通道分布和活性改变，这导致了神经退行性变。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99a6/10382591/7a63748e1afe/41467_2023_39937_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99a6/10382591/18b3311f35b4/41467_2023_39937_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99a6/10382591/091ebefd6d22/41467_2023_39937_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99a6/10382591/a10274421f4c/41467_2023_39937_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99a6/10382591/aac5170780c8/41467_2023_39937_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99a6/10382591/57b5b056b34e/41467_2023_39937_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99a6/10382591/f9da8aa56076/41467_2023_39937_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99a6/10382591/803daaadcba6/41467_2023_39937_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99a6/10382591/517425a4d5ba/41467_2023_39937_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99a6/10382591/2c88efdc8427/41467_2023_39937_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99a6/10382591/7a63748e1afe/41467_2023_39937_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99a6/10382591/18b3311f35b4/41467_2023_39937_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99a6/10382591/091ebefd6d22/41467_2023_39937_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99a6/10382591/a10274421f4c/41467_2023_39937_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99a6/10382591/aac5170780c8/41467_2023_39937_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99a6/10382591/57b5b056b34e/41467_2023_39937_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99a6/10382591/f9da8aa56076/41467_2023_39937_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99a6/10382591/803daaadcba6/41467_2023_39937_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99a6/10382591/517425a4d5ba/41467_2023_39937_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99a6/10382591/2c88efdc8427/41467_2023_39937_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99a6/10382591/7a63748e1afe/41467_2023_39937_Fig10_HTML.jpg

相似文献

[1]
NPC1-dependent alterations in K2.1-Ca1.2 nanodomains drive neuronal death in models of Niemann-Pick Type C disease.

Nat Commun. 2023-7-28

[2]
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[3]
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[4]
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[5]
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[6]
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[7]
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[8]
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[9]
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[10]
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引用本文的文献

[1]
Heterozygosity in NPC may be associated with neurologic and systemic phenotypes.

Front Neurol. 2025-8-12

[2]
Lysosome-Mitochondrial Crosstalk in Cellular Stress and Disease.

Antioxidants (Basel). 2025-1-22

[3]
OSBP Participates in Neural Damage Repair by Regulating Lysosome Transport Under Oxidative Stress.

Mol Neurobiol. 2025-6

[4]
Unifying biology of neurodegeneration in lysosomal storage diseases.

J Inherit Metab Dis. 2025-1

[5]
Channels, Transporters, and Receptors at Membrane Contact Sites.

Contact (Thousand Oaks). 2024-12-26

[6]
High-Resolution Proteomics Unravel a Native Functional Complex of Cav1.3, SK3, and Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels in Midbrain Dopaminergic Neurons.

Cells. 2024-5-30

[7]
Nano-organization of synaptic calcium signaling.

Biochem Soc Trans. 2024-6-26

[8]
Unraveling the Connection: Cholesterol, Calcium Signaling, and Neurodegeneration.

Neurosci Insights. 2024-5-11

[9]
α-Synuclein-dependent increases in PIP5K1γ drive inositol signaling to promote neurotoxicity.

Cell Rep. 2023-10-31

本文引用的文献

[1]
Acute phosphatidylinositol 4,5 bisphosphate depletion destabilizes sarcolemmal expression of cardiac L-type Ca channel Ca1.2.

Proc Natl Acad Sci U S A. 2023-4-4

[2]
Endoplasmic Reticulum-Plasma Membrane Junctions as Sites of Depolarization-Induced Ca Signaling in Excitable Cells.

Annu Rev Physiol. 2023-2-10

[3]
Activity-dependent endoplasmic reticulum Ca uptake depends on Kv2.1-mediated endoplasmic reticulum/plasma membrane junctions to promote synaptic transmission.

Proc Natl Acad Sci U S A. 2022-7-26

[4]
The E3 Ubiquitin Ligase CRL5 Regulates Dentate Gyrus Morphogenesis, Adult Neurogenesis, and Animal Behavior.

Front Neurosci. 2022-6-21

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Physiol Rev. 2022-7-1

[6]
Regulation of neuronal excitation-transcription coupling by Kv2.1-induced clustering of somatic L-type Ca channels at ER-PM junctions.

Proc Natl Acad Sci U S A. 2021-11-16

[7]
IPR-driven increases in mitochondrial Ca promote neuronal death in NPC disease.

Proc Natl Acad Sci U S A. 2021-10-5

[8]
NPC1 regulates the distribution of phosphatidylinositol 4-kinases at Golgi and lysosomal membranes.

EMBO J. 2021-7-1

[9]
Cholesterol transport between cellular membranes: A balancing act between interconnected lipid fluxes.

Dev Cell. 2021-5-17

[10]
Inositol triphosphate-triggered calcium release blocks lipid exchange at endoplasmic reticulum-Golgi contact sites.

Nat Commun. 2021-5-11

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