Biological interacting units identified in human protein networks reveal tissue-functional diversification and its impact on disease

García-Vaquero, Marina L.; Gama‐Carvalho, Margarida; Pinto, Francisco; Rivas, Javier De Las

doi:10.1016/j.csbj.2022.07.006

Cited by 2 publications

(3 citation statements)

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“…To understand whether the phenotypic commonalities observed in ALS and SMA might result from the deregulation of distinct, but functionally connected target proteins, we used a computational network-based approach. First, following our recently published approach [ 69 ], we generated a library of tissue-specific "functional modules" comprised of physically interacting and functionally collaborating neuronal proteins (Fig. 3 A).…”

Section: Resultsmentioning

confidence: 99%

“…To investigate this possibility, we mapped the de-regulated transcripts identified in our transcriptomic analysis onto a comprehensive and non-biased library of neuronal physically interacting and functionally collaborating protein consortia. Following our recently published approach [ 69 ], definition of these functional units was achieved through the integration publicly available information from Drosophila PPI networks, neuronal gene expression and gene ontology annotations. This approach led to the identification of a set of 52 functional modules significantly impacted by all three proteins through the regulation of distinct components (Fig.…”

Section: Discussionmentioning

confidence: 99%

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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,

Heim,

Flix

et al. 2023

BMC Genomics

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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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Garcia-Vaquero,

Heim,

Flix

et al. 2023

BMC Genomics

Self Cite

View full text Add to dashboard Cite

show abstract

“…To understand whether the phenotypic commonalities observed in ALS and SMA might result from the deregulation of distinct, but functionally connected target proteins, we used a computational network-based approach. First, following our recently published approach (Garcia-Vaquero et al 2022), we generated a library of tissue-specific “functional modules” comprised of physically interacting and functionally collaborating neuronal proteins (Fig. 3A).…”

Section: Resultsmentioning

confidence: 99%

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

García-Vaquero

Heim

Flix

et al. 2022

Preprint

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Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis share both phenotypic and molecular commonalities, including the fact that they can be caused by mutations in 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 converging motoneuron dysfunction caused by changes in the expression of these ubiquitous genes. In this work we generated a parallel set of Drosophila models for adult-onset RNAi and tagged neuronal expression of the orthologues of SMN1, TARDBP and FUS (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. Our integrative approach revealed that although each disease-associated gene regulates a poorly overlapping set of transcripts, they have a concerted effect on a specific subset of protein functional modules, acting through distinct targets. Most strikingly, functional annotation reveals these modules to be involved in critical cellular pathways for neurons and in particular, in neuromuscular junction function. Furthermore, selected modules were found to be significantly enriched in orthologues of human genes linked to neuronal disease. This work provides a new model explaining how mutations in SMA and ALS-associated disease genes linked to RNA metabolism functionally converge to cause motoneuron dysfunction. The critical functional modules identified represent interesting biomarkers and therapeutic targets given their identification in asymptomatic disease models.

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Biological interacting units identified in human protein networks reveal tissue-functional diversification and its impact on disease

Cited by 2 publications

References 42 publications

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

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

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

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