Suchergebnisse

Type-2 diabetes (T2D) and glucose metabolic imbalances have been linked to neurodegenerative diseases, including Parkinson's disease (PD). To detect potential effects of different glucose levels on gene expression, by RNA-seq we analyzed the transcriptome of dermal fibroblasts from idiopathic PD (iPD) patients, LRRK2-associated PD (L2PD) patients, and healthy controls (total n = 21 cell lines), which were cultured at two different glucose concentrations (25 and 5 mM glucose). In PD patients we identified differentially expressed genes (DEGs) that were related to biological processes mainly involving the plasmatic cell membrane, the extracellular matrix, and also neuronal functions. Such pathway deregulation was largely similar in iPD or L2PD fibroblasts. Overall, the gene expression changes detected in this study were associated with PD independently of glucose concentration. ; This work was supported by CIBERNED / Instituto de Salud Carlos III (ISCIII) (grant PIE14/00061) (to M.-J.M.), and the Fondo de Investigaciones Sanitarias from ISCIII (grant PIE20/00259) (to M.E.). R.F.-S. was supported by a Jóvenes Investigadores (JIN) grant of the Spanish Ministry of Economy and Competitiveness (MINECO) and the Agencia Estatal de Investigación (AEI) (AEI/FEDER/UE) (grant #SAF2015-73508-JIN), and a Miguel Servet grant from the Instituto de Salud Carlos III (grant #CP19/00048). A.E-C. was funded by ISCIII /MINECO (PT17/0009/0019) and co-funded by FEDER. M.F. was funded through a María de Maeztu grant (#MDM-2017-0729). IDIBAPS receives funding from the CERCA Program from the Generalitat de Catalunya and the FEDER Program from the European Union.

Idiopathic Parkinson's disease (iPD) and type 2 diabetes mellitus (T2DM) are chronic, multisystemic, and degenerative diseases associated with aging, with eventual epidemiological co-morbidity and overlap in molecular basis. This study aims to explore if metabolic and mitochondrial alterations underlie the previously reported epidemiologic and clinical co-morbidity from a molecular level. To evaluate the adaptation of iPD to a simulated pre-diabetogenic state, we exposed primary cultured fibroblasts from iPD patients and controls to standard (5 mM) and high (25 mM) glucose concentrations to further characterize metabolic and mitochondrial resilience. iPD fibroblasts showed increased organic and amino acid levels related to mitochondrial metabolism with respect to controls, and these differences were enhanced in high glucose conditions (citric, suberic, and sebacic acids levels increased, as well as alanine, glutamate, aspartate, arginine, and ornithine amino acids; p-values between 0.001 and 0.05). The accumulation of metabolites in iPD fibroblasts was associated with (and probably due to) the concomitant mitochondrial dysfunction observed at enzymatic, oxidative, respiratory, and morphologic level. Metabolic and mitochondrial plasticity of controls was not observed in iPD fibroblasts, which were unable to adapt to different glucose conditions. Impaired metabolism and mitochondrial activity in iPD may limit energy supply for cell survival. Moreover, reduced capacity to adapt to disrupted glucose balance characteristic of T2DM may underlay the co-morbidity between both diseases. Conclusions: Fibroblasts from iPD patients showed mitochondrial impairment, resulting in the accumulation of organic and amino acids related to mitochondrial metabolism, especially when exposed to high glucose. Mitochondrial and metabolic defects down warding cell plasticity to adapt to changing glucose bioavailability may explain the comorbidity between iPD and T2DM. ; This work was supported by funds from the Integrated Projects of Excellence PIE14/00061 and the Fondo de Investigaciones Sanitarias of the Instituto de Salud Carlos III (ISCIII) (grant numbers PI1800498 and PI1800451), the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), all initiatives of ISCIII and FEDER ('Una manera de hacer Europa'), as well as Fundació Privada Cellex and Suports a Grups de Recerca (grant code 2017 SGR 893) and CERCA programs from the Generalitat de Catalunya. Maria de Maeztu Unit of Excellence funded our institution (Institute of Neurosciences, University of Barcelona) as consolidated excellence centre (MDM-2017-0729, Ministry of Science, Innovation and Universities). Two grants from the Spanish government allowed facility maintenance (SAF2017-85877-R from CGR and both SAF2015-69944-R and PID2019-111669RB-I00 from JCFC) ; Peer reviewed