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Analysis of asymptomatic Drosophila models for ALS and SMA reveals convergent impact on functional protein complexes linked to neuro-muscular degeneration.
Garcia-Vaquero, Marina L; Heim, Marjorie; Flix, Barbara; Pereira, Marcelo; Palin, Lucile; Marques, Tânia M; Pinto, Francisco R; de Las Rivas, Javier; Voigt, Aaron; Besse, Florence; Gama-Carvalho, Margarida.
Affiliation
  • Garcia-Vaquero ML; BioISI - Institute for Biosystems and Integrative Sciences, Faculty of Sciences, University of Lisbon, 1749-016, Lisbon, Portugal.
  • Heim M; Department of Medicine and Cytometry General Service-15 Nucleus, Cancer Research Centre (IBMCC/CSIC/USAL/IBSAL), CIBERONC, 16 37007, Salamanca, Spain.
  • Flix B; Institut de Biologie Valrose, Université Côte d'Azur, CNRS, 06108, Nice, Inserm, France.
  • Pereira M; Department of Neurology, Medical Faculty, RWTH Aachen University, 52074, Aachen, Germany.
  • Palin L; BioISI - Institute for Biosystems and Integrative Sciences, Faculty of Sciences, University of Lisbon, 1749-016, Lisbon, Portugal.
  • Marques TM; Institut de Biologie Valrose, Université Côte d'Azur, CNRS, 06108, Nice, Inserm, France.
  • Pinto FR; BioISI - Institute for Biosystems and Integrative Sciences, Faculty of Sciences, University of Lisbon, 1749-016, Lisbon, Portugal.
  • de Las Rivas J; BioISI - Institute for Biosystems and Integrative Sciences, Faculty of Sciences, University of Lisbon, 1749-016, Lisbon, Portugal.
  • Voigt A; Cancer Research Center (CiC-IBMCC, CSIC/USAL/IBSAL), Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca (USAL), 37007, Salamanca, Spain.
  • Besse F; Department of Neurology, Medical Faculty, RWTH Aachen University, 52074, Aachen, Germany.
  • Gama-Carvalho M; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH RWTH Aachen University, 52074, Aachen, Germany.
BMC Genomics ; 24(1): 576, 2023 Sep 27.
Article in En | MEDLINE | ID: mdl-37759179
ABSTRACT

BACKGROUND:

Spinal 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.

RESULTS:

Transcriptome 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.

CONCLUSIONS:

The 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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Muscular Atrophy, Spinal / Drosophila Proteins / Amyotrophic Lateral Sclerosis Type of study: Prognostic_studies Limits: Adult / Animals / Humans Language: En Journal: BMC Genomics Journal subject: GENETICA Year: 2023 Document type: Article Affiliation country:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Muscular Atrophy, Spinal / Drosophila Proteins / Amyotrophic Lateral Sclerosis Type of study: Prognostic_studies Limits: Adult / Animals / Humans Language: En Journal: BMC Genomics Journal subject: GENETICA Year: 2023 Document type: Article Affiliation country: