Dataset Information

Proteomics analysis zebrafish ALS model

ABSTRACT: Despite advances in studies of C9orf72-ALS, understanding the function of C9orf72 remains a key research element that is poorly explored. We generated a C9orf72-related ALS stable zebrafish line with a reduced expression of C9orf72.Using this stable transgenic zebrafish model, we analyzed the effects of reduced C9orf72 function on the zebrafish’s neuromuscular system.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Danio Rerio (zebrafish) (brachydanio Rerio)

TISSUE(S): Whole Body

DISEASE(S): Amyotrophic Lateral Sclerosis

SUBMITTER: Kessen Patten

LAB HEAD: Kessen Patten

PROVIDER: PXD025850 | Pride | 2022-02-17

REPOSITORIES: Pride

ACCESS DATA

Publications

Reduced C9orf72 function leads to defective synaptic vesicle release and neuromuscular dysfunction in zebrafish.

Butti Zoé Z Pan Yingzhou Edward YE Giacomotto Jean J Patten Shunmoogum A SA

Communications biology 20210625 1

The most common genetic cause of amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) is a hexanucleotide repeat expansion within the C9orf72 gene. Reduced levels of C9orf72 mRNA and protein have been found in ALS/FTD patients, but the role of this protein in disease pathogenesis is still poorly understood. Here, we report the generation and characterization of a stable C9orf72 loss-of-function (LOF) model in the zebrafish. We show that reduced C9orf72 function leads to motor d ...[more]

PMID: 34172817

Similar Datasets

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.

Dataset Information

Proteomics analysis zebrafish ALS model

Publications

Reduced C9orf72 function leads to defective synaptic vesicle release and neuromuscular dysfunction in zebrafish.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure