Dataset Information

MicroRNA137-loaded lipid nanoparticles regulate synaptic proteins in the prefrontal cortex

ABSTRACT: Genome-wide association studies indicate allele variants in MIR137, the host gene of microRNA-137 (miR137), confer an increased risk of schizophrenia (SCZ). Expression of miR137 and its targets, many of which regulate synaptic functioning, are also associated with an increased risk of SCZ. As a result, miR137 represents an attractive target aimed at correcting the molecular basis for synaptic dysfunction in individuals with high genetic risk for SCZ. Advancements in nanotechnology utilize lipid nanoparticles (LNPs) to transport and deliver therapeutic RNA. However, there remains a gap in using LNPs to regulate gene and protein expression in the brain. To study the delivery of nucleic acids by LNPs to the brain, we found that LNPs released miR137 cargo and inhibited synaptic target transcripts in neuronal cultures. Biodistribution of LNPs loaded with firefly luciferase mRNA remained localized to the mouse prefrontal cortex (PFC) injection site without circulating to off-target organs. LNPs encapsulating Cre mRNA preferentially co-expressed in neuronal over microglial or astrocytic cells. Using quantitative proteomics, we found miR137 modulated glutamatergic synaptic protein networks that are commonly dysregulated in SCZ. These studies support engineering the next generation of brain-specific LNPs to deliver personalized RNA therapeutics and improve symptoms of central nervous system disorders.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Phillip Wilmarth

LAB HEAD: Aaron Janowsky, Ph.D.

PROVIDER: PXD041648 | Pride | 2023-09-05

REPOSITORIES: Pride

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Publications

MicroRNA137-loaded lipid nanoparticles regulate synaptic proteins in the prefrontal cortex.

Palumbo Michelle C MC Gautam Milan M Sonneborn Alex A Kim Kilsun K Wilmarth Phillip A PA Reddy Ashok P AP Shi Xiao X Marks Daniel L DL Sahay Gaurav G Abbas Atheir I AI Janowsky Aaron A

Molecular therapy : the journal of the American Society of Gene Therapy 20230828 10

Genome-wide association studies indicate that allele variants in MIR137, the host gene of microRNA137 (miR137), confer an increased risk of schizophrenia (SCZ). Aberrant expression of miR137 and its targets, many of which regulate synaptic functioning, are also associated with an increased risk of SCZ. Thus, miR137 represents an attractive target aimed at correcting the molecular basis for synaptic dysfunction in individuals with high genetic risk for SCZ. Advancements in nanotechnology utilize ...[more]

PMID: 37644723

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Project description:The study was designed in order to identify genes differentially expressed when glucocorticoid signaling is blocked by a glucocorticoid-receptor antagonist (RU486 â?? mifepristone) in the context of brain inflammation induced by bacterial lipopolysaccharide (LPS). LPS is only able to cause murine brain damage in our experimental conditions upon RU486 pre-treatment. Hence, the study may reveal potential candidate genes to mediate neuroprotection or neurotoxicity. Due to the factorial design of the experiment, RU486 main-effect could be dissociated from the effects resultant of RU486/inflammation interaction. In addition, brain dissection was conducted to verify the effects in the brain side ipsilateral or contralateral to the site of intracerebral LPS infusion. Experiment Overall Design: C57Bl/6 mice received an i.p. injection of vehicle (DMSO - 50 microliters) or RU486 (50 mg/kg) and were submitted to surgery 4 h later. The mice receiving intraparenchymal injections were anesthetized and the right caudate putamen was reached, using a small cannula at the coordinates 0.0 mm anteroposterior, -2.0 mm lateral, and -3.0 mm dorsoventral according to a mouse brain atlas. The animals received an infusion of sterile pyrogen-free saline (1 microliter) or LPS (from Eschericia coli; serotype O55:B5; Sigma L2880 - 2.5 micrograms) over 2 min by means of a microinjection 18 pump. Animals were killed 12 h after the intracerebral infusion. The mice were anesthetized under isofluorane and blood was drawn via cardiac puncture before head decapitation. Brains were removed rapidly from the skulls and placed in cold phosphate buffered saline (PBS) solution. A brain region limited at plane anteroposterior +1.5 to -1.5 and dorsoventral -4.0 was dissected, separated in ipsilateral side and quickly immersed in liquid nitrogen. The tissue was stored at -80 oC until RNA extraction was performed. A total of 37 chips (MOE430A â?? Affymetrix, Santa Clara, CA) were used for oligonucleotide array analysis [one chip per biological sample; 8 groups (contralateral dmso/saline, dmso/LPS, RU486/saline, RU486/LPS and ipsilateral dmso/saline, dmso/LPS, RU486/saline, RU486/LPS) with 4 â?? 6 biological replicates each]. Expression values from the CEL files generated from scanning were obtained using RMA algorithm, available at http://www.bioconductor.org. The expression values were also inspected with GeneSpring software (Silicon Genetics). Statistical analysis was performed considering a factorial linear model according to the methods implemented in Limma package (R project packages are available at http://www.cran.r-project.org).

Dataset Information

MicroRNA137-loaded lipid nanoparticles regulate synaptic proteins in the prefrontal cortex

Publications

MicroRNA137-loaded lipid nanoparticles regulate synaptic proteins in the prefrontal cortex.

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