Title : Molecular characterization of fibroblasts’ models of neurologic and neuromuscular diseases
Introduction: Both neurologic and neuromuscular diseases as Parkinson disease (PD) and sporadic inclusion body myositis (sIBM) usually affect patients at elderly stages of life and share common molecular etiology. Inflammation, proteostasis deregulation, degenerative autophagic changes, oxidative stress, metabolic and bioenergetic dysfunction have been reported, among others, in both kind of disorders. Unfortunately, most of these diseases lack either diagnostic/prognostic biomarkers and effective treatments, mainly due to the lack of validated disease models. We aim to validate fibroblasts as a disease model for both kind of disorders to set the path for further advances.
Methodology: We examined PD and IBM disease hallmarks in fibroblasts of affected patients using OMICs and functional approaches. In OMICs approach, we analyzed the transcriptome and metabolic profile in fibroblasts from 6-8 PD patients, 14 sIBM subjects and 12 paired controls, through mRNA seq and UHPLC (Ultra High-Performance Liquid Chromatography). In the functional approach, we assessed inflammatory, degenerative, oxidative stress, metabolic and bioenergetic changes in patients’ fibroblasts. Results were analyzed through non-parametric statistic tests.
Results: In the OMICs approach, 343 and 778 deregulated expressed genes were found in PD and sIBM patients’ fibroblasts, in pathways related to cell adhesion, cell growth, amino acid and folate metabolism (in PD), or RNA processing, cell communication and amino acid metabolism (in sIBM). UHPLC showed altered amino acid and organic acid levels related to mitochondrial defects and Krebs cycle in both kind of fibroblasts. In the functional approach, PD and sIBM fibroblasts showed different but both dysfunctional profiles characterized by increased secretion of cytokines, defective autophagy, increased oxidative stress and deregulated metabolic and bioenergetic status that may underscore cell feat.
Conclusion: Both OMICs and functional approaches recapitulate PD and sIBM hallmarks in fibroblasts, thus validating its usefulness as a disease model to explore molecular targets and assay therapeutic strategies that may eventually be exported to other neurologic and neuromuscular diseases. Our findings indeed support the view of PD and sIBM as ‘systemic diseases’ affecting also peripheral tissues such as the skin.