Dataset Information

Multi-omics reveals the lipid inventory of synaptic junctions and altered lipid signaling in environmental enrichment

ABSTRACT: Membrane lipids are essential components of synaptic junctions that have key functions in neurotransmission. In the first part of the study, we provide a quantitative lipid inventory of mouse and rat synaptic junctions. We next used a simultaneous multi-omics extraction and analysis workflow termed SIMPLEX to probe the interplay of proteins and lipids in synaptic signal transduction. We found that SIMPLEX is suitable to generate hypotheses about novel mechanisms underlying complex changes in synaptic connectivity elicited by environmental stimuli. As a proof of principle, this approach revealed that in mice exposed to an enriched environment reduced endocannabinoid signaling is linked to increased surface expression of AMPAR in a subset of Cannabinoid-receptor 1 positive synapses, a mechanism which likely regulates synaptic strength in an input-specific manner.

INSTRUMENT(S): LTQ Orbitrap, Q Exactive HF

ORGANISM(S): Rattus Norvegicus (rat) Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Canan Has

LAB HEAD: Robert Ahrends

PROVIDER: PXD017997 | Pride | 2023-11-14

REPOSITORIES: pride

ACCESS DATA

Dataset's files

Source:

Items per page:

1 - 5 of 28

Publications

Multiomics of synaptic junctions reveals altered lipid metabolism and signaling following environmental enrichment.

Borgmeyer Maximilian M Coman Cristina C Has Canan C Schött Hans-Frieder HF Li Tingting T Westhoff Philipp P Cheung Yam F H YFH Hoffmann Nils N Yuanxiang PingAn P Behnisch Thomas T Gomes Guilherme M GM Dumenieu Mael M Schweizer Michaela M Chocholoušková Michaela M Holčapek Michal M Mikhaylova Marina M Kreutz Michael R MR Ahrends Robert R

Cell reports 20211001 1

Membrane lipids and their metabolism have key functions in neurotransmission. Here we provide a quantitative lipid inventory of mouse and rat synaptic junctions. To this end, we developed a multiomics extraction and analysis workflow to probe the interplay of proteins and lipids in synaptic signal transduction from the same sample. Based on this workflow, we generate hypotheses about novel mechanisms underlying complex changes in synaptic connectivity elicited by environmental stimuli. As a proo ...[more]

PMID: 34610315

Similar Datasets

Project description:Local translation at the synapse plays key roles in neuron development and activity-dependent synaptic plasticity. mRNAs are translocated from the neuronal soma to the distant synapses as compacted ribonucleoparticles referred to as RNA granules. These contain many RNA-binding proteins, including the Fragile X Mental Retardation Protein (FMRP), the absence of which results in Fragile X Syndrome, the most common inherited form of intellectual disability and the leading genetic cause of autism. Using FMRP as a tracer, we purified a specific population of RNA granules from mouse brain homogenates. Protein composition analyses revealed a strong relationship between polyribosomes and RNA granules. However, the latter have distinct architectural and structural properties, since they are detected as close compact structures as observed by electron microscopy, and converging evidence point to the possibility that these structures emerge from stalled polyribosomes. Time-lapse video microscopy indicated that single granules merge to form cargoes that are transported from the soma to distal locations. Transcriptomic analyses showed that a subset of mRNAs involved in cytoskeleton remodelling and neural development is selectively enriched in RNA granules. One third of the putative mRNA targets described for FMRP appear to be transported in granules and FMRP is more abundant in granules than in polyribosomes. This observation supports a primary role for FMRP in granules biology. Our findings open new avenues for the study of RNA granule dysfunctions in animal models of nervous system disorders, such as Fragile X syndrome. Fragile X syndrome is the most common form of inherited mental retardation affecting approximately 1 female out of 7000 and 1 male out of 4000 worldwide. The syndrome is due to the silencing of a single gene, the Fragile Mental Retardation 1 (FMR1), that codes for the Fragile X mental retardation protein (FMRP). This protein is highly expressed in brain and controls local protein synthesis essential for neuronal development and maturation as well as the formation of neural circuits. Several studies suggest a role for FMRP in the regulation of mRNA transport along axons and dendrites to distant synaptic locations in structures called RNA granules. Here we report the isolation of a particular subpopulation of these structures and the analysis of their architecture and composition in terms of RNA and protein. Also, using time-lapse video microscopy, we monitored granule transport and fusion throughout neuronal processes. These findings open new avenues for the study of RNA transport dysfunctions in animal models of nervous system disorders. The control or reference structure or subcellular fraction are the neuronal polyribosomes while the experimental or test structure or subcellular fraction are the neuronal granules. Three independant replicates were done for each structure. Microarray hybridization was done using a two-color design in full dye-swap.

Project description:Increasing evidence suggests synaptic dysfunction is a central and possibly triggering factor in Amyotrophic Lateral Sclerosis (ALS). Despite this, we still know very little about the molecular profile of an ALS synapse. To address this gap, we designed a synaptic proteomics experiment to perform an unbiased assessment of the synaptic proteome in the ALS brain. We isolated synaptoneurosomes from fresh-frozen postmortem human cortex (11 controls and 18 ALS) and stratified the ALS group based on cognitive profile (Edinburgh Cognitive and Behavioural ALS Screen (ECAS score)) and presence of a C9ORF72 hexanucleotide repeat expansion (C9ORF72 -RE). This allowed us to assess regional differences and the impact of phenotype and genotype on the synaptic proteome, using Tandem Mass Tagging-based proteomics. We identified over 6000 proteins in our synaptoneurosomes and using robust bioinformatics analysis we validated the strong enrichment of synapses. We found more than 30 ALS-associated proteins in synaptoneurosomes, including TDP-43, FUS, SOD1 and C9ORF72. We identified almost 500 proteins with altered expression levels in ALS, with region-specific changes highlighting proteins and pathways with intriguing links to neurophysiology and pathology. Stratifying the ALS cohort by cognitive status revealed almost 150 specific alterations in cognitively impaired ALS synaptic preparations. Stratifying by C9ORF72 -RE status revealed 330 protein alterations in the C9ORF72 -RE+ve group, with KEGG pathway analysis highlighting strong enrichment for postsynaptic dysfunction, related to glutamatergic receptor signalling. We have validated some of these changes by western blot and at a single synapse level using array tomography imaging. In summary, we have generated the first unbiased map of the human ALS synaptic proteome, revealing novel insight into this key compartment in ALS pathophysiology and highlighting the influence of cognitive decline and C9ORF72 -RE on synaptic composition.

			Action	DRS
	F058132.dat	Other
	Lip06_0806_globalno_normalization.msf	Msf
	Lumos00330.raw	Raw
	Lumos00331.raw	Raw
	Lumos00332.raw	Raw