RESUMEN
Monogenic diseases are well-suited paradigms for the causal analysis of disease-driving molecular patterns. Spinal Muscular Atrophy (SMA) is one such monogenic model caused by mutation or deletion of the Survival of motor neuron 1 (SMN1) gene. Although several functions of the SMN protein have been studied, single functions and pathways alone do not allow to identify critical disease-driving molecules. Here, we analyzed the systemic characteristics of SMA employing proteomics, phosphoproteomics, translatomics and interactomics from two mouse models with different disease-severities and genetics. This systems approach revealed sub-networks and proteins characterizing commonalities and differences of both models. To link the identified molecular networks with the disease-causing SMN protein, we combined SMN-interactome data with both proteomes creating a comprehensive representation of SMA. By this approach, disease hubs and bottlenecks between SMN and downstream pathways could be identified. Linking a disease-causing molecule with widespread molecular dysregulations via multiomics is a concept for analyses of monogenic diseases.
RESUMEN
Spinal Muscular Atrophy (SMA), a neurodegenerative disorder, extends its impact beyond the nervous system. The central protein implicated in SMA, Survival Motor Neuron (SMN) protein, is ubiquitously expressed and functions in fundamental processes such as alternative splicing, translation, cytoskeletal dynamics and signaling. These processes are relevant for all cellular systems, including cells of the immune system such as macrophages. Macrophages are capable of modulating their splicing, cytoskeleton and expression profile in order to fulfil their role in tissue homeostasis and defense. However, less is known about impairment or dysfunction of macrophages lacking SMN and the subsequent impact on the immune system of SMA patients. We aimed to review the potential overlaps between SMN functions and macrophage mechanisms highlighting the need for future research, as well as the current state of research addressing the role of macrophages in SMA.
Asunto(s)
Macrófagos , Atrofia Muscular Espinal , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/inmunología , Animales , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Proteína 1 para la Supervivencia de la Neurona Motora/metabolismo , Transducción de SeñalRESUMEN
Spinal Muscular Atrophy is caused by partial loss of survival of motoneuron (SMN) protein expression. The numerous interaction partners and mechanisms influenced by SMN loss result in a complex disease. Current treatments restore SMN protein levels to a certain extent, but do not cure all symptoms. The prolonged survival of patients creates an increasing need for a better understanding of SMA. Although many SMN-protein interactions, dysregulated pathways, and organ phenotypes are known, the connections among them remain largely unexplored. Monogenic diseases are ideal examples for the exploration of cause-and-effect relationships to create a network describing the disease-context. Machine learning tools can utilize such knowledge to analyze similarities between disease-relevant molecules and molecules not described in the disease so far. We used an artificial intelligence-based algorithm to predict new genes of interest. The transcriptional regulation of 8 out of 13 molecules selected from the predicted set were successfully validated in an SMA mouse model. This bioinformatic approach, using the given experimental knowledge for relevance predictions, enhances efficient targeted research in SMA and potentially in other disease settings.
Asunto(s)
Inteligencia Artificial , Biología Computacional , Modelos Animales de Enfermedad , Atrofia Muscular Espinal , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/metabolismo , Animales , Ratones , Humanos , Biología Computacional/métodos , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Proteína 1 para la Supervivencia de la Neurona Motora/metabolismo , Aprendizaje Automático , Algoritmos , Regulación de la Expresión Génica/genéticaRESUMEN
Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by decreased levels of the survival of motoneuron (SMN) protein. Post-translational mechanisms for regulation of its stability are still elusive. Thus, we aimed to identify regulatory phosphorylation sites that modulate function and stability. Our results show that SMN residues S290 and S292 are phosphorylated, of which SMN pS290 has a detrimental effect on protein stability and nuclear localization. Furthermore, we propose that phosphatase and tensin homolog (PTEN), a novel phosphatase for SMN, counteracts this effect. In light of recent advancements in SMA therapies, a significant need for additional approaches has become apparent. Our study demonstrates S290 as a novel molecular target site to increase the stability of SMN. Characterization of relevant kinases and phosphatases provides not only a new understanding of SMN function, but also constitutes a novel strategy for combinatorial therapeutic approaches to increase the level of SMN in SMA.