A systems approach to the mechanism os neurodegeneration

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A systems approach to the mechanisms of neurodegeneration

Publication . García-Vaquero, Marina L.; Carvalho, Margarida Henriques da Gama; De Las Rivas, Javier

Motor neuron diseases (MND) encompass a spectrum of motor neuron (MN) degenerative conditions associated to numerous genetic alterations, the most common of which are ALS and SMA-5q. Despite years of research, the molecular mechanisms underlying MN degeneration remain unclear. The present work aimed to contribute to answer two outstanding questions: 1) how do MND phenotypes arise from changes in distinct cellular pathways; and 2) how can the alteration of ubiquitously expressed proteins generate MNspecific diseases. We made use of network biology principles to investigate the tissuespecific interactomic context of MND genes and elucidate transversal characteristics shared by distinct MNDs. Two novel network-based methods were developed to characterize the functional landscape of tissue-specific interactomes (BioInt-U); and to identify bottleneck proteins connecting pairs of diseases with similar phenotypes (S2B). The application of the BioInt-U method to human PPI networks revealed tissue-specific functional specialization of ubiquitous proteins, with effective prediction of disease phenotypes. The S2B method was applied to prioritize candidates connecting ALS and SMA-linked genes in human and Drosophila brain networks, revealing coherent functional roles. RNA-seq data from Drosophila models was used to identify neuronal genes that are directly and indirectly regulated by the fly orthologs of the ALS and SMA causal genes TARDBP, FUS and SMN1. This work revealed a phenotypic convergence onto common protein functional modules, albeit through independent targets. In conjugation with the BioInt method, it further provided insights into the origin of MN specific phenotypes. Finally, the candidate genes identified in human and Drosophila networks using S2B and Drosophila transcriptome data, complemented by a publicly available dataset from ALS patients, were subjected to an integrative analysis by mapping onto BioInt units. Taken together, the work presented here provides novel insights regarding the molecular mechanisms underlying MNDs, while developing computational methods that can be used to address other diseases.

2022-12Tese de doutoramento

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Entidade financiadora

Fundação para a Ciência e a Tecnologia

Programa de financiamento

OE

Número da atribuição

PD/BD/128109/2016