Analysis of asymptomatic Drosophila models for ALS and SMA reveals convergent impact on functional protein complexes linked to neuro-muscular degeneration

BMC Genomics

Research

Tânia M. Marques¹  Marcelo Pereira¹  Francisco R. Pinto¹  Margarida Gama-Carvalho¹  Marina L. Garcia-Vaquero²  Javier de Las Rivas³  Barbara Flix⁴  Aaron Voigt⁵  Marjorie Heim⁶  Florence Besse⁶  Lucile Palin⁶ 

[1] BioISI – Institute for Biosystems and Integrative Sciences, Faculty of Sciences, University of Lisbon, 1749-016, Lisbon, Portugal;BioISI – Institute for Biosystems and Integrative Sciences, Faculty of Sciences, University of Lisbon, 1749-016, Lisbon, Portugal;Department of Medicine and Cytometry General Service-15 Nucleus, Cancer Research Centre (IBMCC/CSIC/USAL/IBSAL), CIBERONC, 16 37007, Salamanca, Spain;Cancer Research Center (CiC-IBMCC, CSIC/USAL/IBSAL), Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca (USAL), 37007, Salamanca, Spain;Department of Neurology, Medical Faculty, RWTH Aachen University, 52074, Aachen, Germany;Department of Neurology, Medical Faculty, RWTH Aachen University, 52074, Aachen, Germany;JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH RWTH Aachen University, 52074, Aachen, Germany;Institut de Biologie Valrose, Université Côte d’Azur, CNRS, 06108, Nice, Inserm, France;

关键词: ALS;    SMA;    Motor neuron;    Drosophila;    SMN;    TDP-43;    FUS;    Transcriptomics;    Network biology;    Neurodegeneration;   

DOI  :  10.1186/s12864-023-09562-4

 received in 2023-05-06, accepted in 2023-08-08,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundSpinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS) share phenotypic and molecular commonalities, including the fact that they can be caused by mutations in ubiquitous proteins involved in RNA metabolism, namely SMN, TDP-43 and FUS. Although this suggests the existence of common disease mechanisms, there is currently no model to explain the resulting motor neuron dysfunction. In this work we generated a parallel set of Drosophila models for adult-onset RNAi and tagged neuronal expression of the fly orthologues of the three human proteins, named Smn, TBPH and Caz, respectively. We profiled nuclear and cytoplasmic bound mRNAs using a RIP-seq approach and characterized the transcriptome of the RNAi models by RNA-seq. To unravel the mechanisms underlying the common functional impact of these proteins on neuronal cells, we devised a computational approach based on the construction of a tissue-specific library of protein functional modules, selected by an overall impact score measuring the estimated extent of perturbation caused by each gene knockdown.ResultsTranscriptome analysis revealed that the three proteins do not bind to the same RNA molecules and that only a limited set of functionally unrelated transcripts is commonly affected by their knock-down. However, through our integrative approach we were able to identify a concerted effect on protein functional modules, albeit acting through distinct targets. Most strikingly, functional annotation revealed that these modules are involved in critical cellular pathways for motor neurons, including neuromuscular junction function. Furthermore, selected modules were found to be significantly enriched in orthologues of human neuronal disease genes.ConclusionsThe results presented here show that SMA and ALS disease-associated genes linked to RNA metabolism functionally converge on neuronal protein complexes, providing a new hypothesis to explain the common motor neuron phenotype. The functional modules identified represent promising biomarkers and therapeutic targets, namely given their alteration in asymptomatic settings.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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