Niemann-Pick type C1 (NPC1) disease is characterized by neurodegeneration caused by cholesterol accumulation in the late endosome/lysosome. In this study, a defective basal and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-stimulated internalization of GluR2-containing AMPA receptors in NPC1-/- cortical neurons was detected. Our results show that the amount of cholesterol and group I metabotropic glutamate receptors (mGluR1/5) in lipid rafts of NPC1-/- cortical tissue and neurons are decreased and their downstream signals of p-ERK are defective, which are restored by a rebalance of cholesterol homeostasis through β-cyclodextrin (β-CD) treatment. Application of 3,5-dihydroxyphenylglycine (DHPG)-a mGluR1/5 agonist-and β-CD markedly increases the internalization of AMPA receptors and decreases over-influx of calcium in NPC1-/- neurons, respectively. Furthermore, the defective phosphorylated GluR2 and protein kinase C signals are ameliorated by the treatment with DHPG and β-CD, respectively, suggesting an involvement of them in internalization dysfunction. Taken together, our data imply that abnormal internalization of AMPA receptors is a critical mechanism for neuronal dysfunction and the correction of dysfunctional mGluR1/5 is a potential therapeutic strategy for NPC1 disease.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1093/cercor/bhz179 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Control of striatal circuit development by the chromatin regulator .
Sci Adv
January 2025
Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
The pathophysiology of neurodevelopmental disorders involves vulnerable neural populations, including striatal circuitry, and convergent molecular nodes, including chromatin regulation and synapse function. Despite this, how epigenetic regulation regulates striatal development is understudied. Recurrent de novo mutations in are associated with intellectual disability and autism.
View Article and Find Full Text PDFNon-canonical Roles of Complement in the CNS: From Synaptic Organizer to Presynaptic Modulator of Glutamate Transmission.
Curr Neuropharmacol
January 2025
Department of Pharmacy, DIFAR, Pharmacology and Toxicology Section, University of Genoa, Viale Cembrano 4, 16148, Genoa, Italy.
The central nervous system (CNS) is not an immune-privileged compartment, but it is intimately intertwined with the immune system. Among the components shared by the two compartments is the complement, a main constituent of innate immunity, which is also produced centrally and controls the development and organization of synaptic connections. Complement is considered a doubled-faced system that, besides controlling the physiological development of the central network, also subserves synaptic engulfment pivotal to the progression of neurodegenerative diseases.
View Article and Find Full Text PDFCationic peptides cause memory loss through endophilin-mediated endocytosis.
Nature
January 2025
Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA.
The zeta inhibitory peptide (ZIP) interferes with memory maintenance and long-term potentiation (LTP) when administered to mice. However, mice lacking its putative target, protein kinase PKMζ, exhibit normal learning and memory as well as LTP, making the mechanism of ZIP unclear. Here we show that ZIP disrupts LTP by removing surface AMPA receptors through its cationic charge alone.
View Article and Find Full Text PDFStructure of transmembrane AMPA receptor regulatory protein subunit γ2.
Nat Commun
January 2025
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Transmembrane AMPA receptor regulatory proteins (TARPs) are claudin-like proteins that tightly regulate AMPA receptors (AMPARs) and are fundamental for excitatory neurotransmission. With cryo-electron microscopy (cryo-EM) we reconstruct the 36 kDa TARP subunit γ2 to 2.3 Å, which points to structural diversity among TARPs.
View Article and Find Full Text PDFThe astrocytic zinc transporter ZIP12 is a synaptic protein that contributes to synaptic zinc levels in mouse auditory cortex.
J Neurosci
January 2025
Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University School of Medicine, Morgantown, WV, USA.
Synaptically released zinc is a neuronal signaling system that arises from the actions of the presynaptic vesicular zinc transporter protein ZnT3. Mechanisms that regulate the actions of zinc at synapses are of great importance for many aspects of synaptic signaling in the brain. Here, we identify the astrocytic zinc transporter protein ZIP12 as a candidate mechanism that contributes to zinc clearance at cortical synapses.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!