Geuna, S. | bioRxiv Science

bioRxiv2024

UnifiedGreatMod: A New Holistic Modeling Paradigm for Studying Biological Systems on a Complete and Harmonious Scale

MotivationComputational models are crucial for addressing critical questions about systems evolution and deciphering system connections. The pivotal feature of making this concept recognisable from the biological and clinical community is the possibility of quickly inspecting the whole system, bearing in mind the different granularity levels of its components. This holistic view of system behaviour expands the evolution study by identifying the heterogeneous behaviours applicable, for example, to the cancer evolution study. ResultsTo address this aspect, we propose a new modelling paradigm, UnifiedGreatMod, which allows modellers to integrate fine-grained and coarse-grained biological information into a unique model. It allows for functional studies, in which the understanding of the systems multi-level stable condition and the systems fluctuating condition are combined to investigate the functional dependencies among the biological entities in the system under study. This is achieved thanks to the hybridisation of two analysis approaches that capture a systems different granularity levels. The proposed paradigm was then implemented into the open-source, general modelling framework GreatMod, in which a graphical meta-formalism is exploited to simplify the model creation phase and R languages to define user-defined analysis workflows. The proposals effectiveness was demonstrated by mechanistically simulating the metabolic output of Echerichia coli under environmental nutrient perturbations and integrating a gene expression dataset. Additionally, the UnifiedGreatMod was used to examine the responses of luminal epithelial cells to Clostridium difficile infection.

systems biology↗

bioRxiv2018

Mice harboring a SCA28 patient mutation in AFG3L2 develop late-onset ataxia associated with enhanced mitochondrial proteotoxicity.

Spinocerebellar ataxia 28 is an autosomal dominant neurodegenerative disorder caused by missense mutations affecting the proteolytic domain of AFG3L2, a major component of the mitochondrial m-AAA protease. However, little is known of the underlying pathogenetic mechanisms or how to treat patients with SCA28. Currently available Afg3l2 mutant mice harbour deletions that lead to severe, early-onset neurological phenotypes that do not faithfully reproduce the late-onset and slowly progressing SCA28 phenotype. Here we describe production and detailed analysis of a new knock-in murine model harbouring an Afg3l2 allele carrying the p.Met665Arg patient-derived mutation. Heterozygous mutant mice developed normally but signs of ataxia were detectable by beam test at 18 months. Cerebellar pathology was negative; electrophysiological analysis showed increased spontaneous firing in Purkinje cells from heterozygous mutants with respect to wild-type controls, although not statistically significant. As homozygous mutants died perinatally with evidence of cardiac atrophy, for each genotype we generated mouse embryonic fibroblasts (MEFs) to investigate mitochondrial function. MEFs from mutant mice showed altered mitochondrial bioenergetics, with decreased basal oxygen consumption rate, ATP synthesis and mitochondrial membrane potential. Mitochondrial network formation and morphology was also altered, in line with greatly reduced expression of Opa1 fusogenic protein L-isoforms. The mitochondrial alterations observed in MEFs were also detected in cerebella of 18-month-old heterozygous mutants, suggesting they may be a hallmark of disease. Pharmacological inhibition of de novo mitochondrial protein translation with chloramphenicol caused reversal of mitochondrial morphology in homozygous mutant MEFs, supporting the relevance of mitochondrial proteotoxicity for SCA28 pathogenesis and therapy development.

genetics↗