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Alessandro Prigione
University Clinic Düsseldorf, Heinrich Heine University, Germany
Abstract: Metabolism is essential for providing the energy necessary to ensure proper cellular function. Mutations in genes regulating this process lead to inherited metabolic disorders that can be organ-specific or multi-organs. Neonatal screenings can identify the presence of a metabolic disorder. However, therapeutic opportunities are only available for a small number of these disorders. Among incurable inherited metabolic diseases, mitochondrial diseases represent a major therapeutic challenges, given that they can be caused by mutations in oxidative phosphorylation genes that are encoded by either the mitochondrial DNA (mtDNA) or the nuclear DNA (nDNA). This fact hampers the generation of effective model systems, given the challenges associated with mtDNA engineering.
In this talk, I will first summarize how stem cell metabolism has emerged as a key aspect associated with the modulation of cell fate transition. I will then present our efforts in using patient-derived induced pluripotent stem cells (iPSCs) to study mitochondrial diseases. We focus primarily on Leigh syndrome, which is the most frequent and most severe mitochondrial disease affecting 1/40,000 newborns. We show that neuronal cultures and brain organoids derived from Leigh syndrome iPSCs can be used as model systems to investigate the disease mechanisms and to carry out phenotypic compound screenings. Our data pave the way to the identification of disease-modifying therapies for currently incurable mitochondrial disorders.
Sinéad A. O’Sullivan, Ayse Ulusoy, Shirley SL Lee, Benjamin Jevans,Donato A. Di Monte
Dept. of Fundamental Research, The German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Abstract: Parkinson’s disease (PD) is characterised by progressive degeneration of dopaminergic cells in the substantia nigra (SN) and is also linked to the accumulation and aggregation of α-synuclein. Clinical and experimental evidence supports a vital role for mitochondrial dysfunction in the pathogenesis of both familial and sporadic PD. Our aim was to develop a quantitative assessment of potential mitochondrial abnormalities at the single-cell level in a mouse model of α-synuclein overexpression. AAVs encoding for human α-synuclein were injected into the SN and after 4 and 12 weeks, immunofluorescent staining revealed that sustained exposure to α-synuclein is associated with a loss of mitochondrial complex I/IV, within dopaminergic neurons. Complex I appears to be more negatively affected than complex IV. Furthermore, our results also indicate that a decreased complex I: Total mitochondria ratio is inversely correlated with the intraneuronal levels of α-synuclein, with this inverse correlation becoming more pronounced at the later timepoint.
Funding: Alexander von Humboldt society, DZNE and the Innovative Medicines Initiative 2 (PDmitoQuant consortium).
A. Stawikowska, M. Magnowska, M. Dziembowska
Laboratory of Molecular Basis of Synaptic Plasticity, Centre of New Technologies University of Warsaw, Poland
Abstract: In the synapse, an important pool of mitochondrial proteins is translated locally on the bases of mRNAs transported from cell soma. Moreover, the local synthesis of proteins constituting mitochondrial respiratory chain complexes is increased by synaptic stimulation. In Fmr1 KO mice, a mouse model of fragile X syndrome, proteomic analysis shows dysregulated levels of mitochondrial proteins. Mitochondrial functions are fundamentally linked to their morphology and inner membrane ultrastructure. We used Serial Block Face-Scanning Electron Microscopy (SBF-SEM) to analyze mitochondrial ultrastructure in the hippocampi of Fmr1 knock-out (KO) and wild-type (WT) male mice. Mitochondria shapes and volumes were reconstructed with the use of RECONSTRUCT software. We compared the morphology and the number of synaptic mitochondria in Fmr1 KO and WT mice. To understand this genetic mutation’s physiological consequences for mitochondrial function in the synapse, we measured the level of reactive oxygen species (ROS) and ATP in mice of three different ages. We found a significant decrease in mitochondrial ROS levels in 13 weeks old Fmr1 KO mice compared to WT mice.
Funding: NCN OPUS 2019/35/B/NZ4/04355
Carla-Ramon Duaso, Laura Vidal-Palencia, Júlia Pinho, Arnau Busquets-Garcia
“Cell-type mechanisms in normal and pathological behavior” Group. IMIM-Hospital del Mar Medical Research Institute, PRBB, Barcelona, SPAIN.
Abstract: Different brain mechanisms have been associated with the pathophysiology of Alzheimer’s disease (AD) including disrupted bioenergetic processes (i.e., mitochondrial dysfunction) and alterations of different components of the endocannabinoid system (ECS). The ECS is considered a key modulator of many brain and body functions, such as cognitive and metabolic processes. Since both, the ECS and brain bioenergetics, have emerged as a potential therapeutic target in AD, we aimed to explore the link between cannabinoids, bioenergetics, and AD. Thus, we conducted a comprehensive sex- and age-dependent behavioral characterization (memory function, social-related behaviors, depressive- and anxiety-like states) in the APP/PS1 mouse AD model after chronic treatment with the CB1 receptor agonist ACEA at 3 months of age (pre-symptomatic stage). Male APP/PS1 mice exhibited a cognitive decline in long-term recognition memory (assessed in the Novel Object Recognition task) that was reversed with the ACEA treatment. In contrast, female APP/PS1 mice showed significant deficits in associative learning (evaluated through a contextual fear conditioning task). Furthermore, we found sex- and brain region-dependent alterations in ECS components and related bioenergetic processes (i.e., OXPHOS, Krebs cycle pathway). Overall, this study sheds light on the relationship between cannabinoids, bioenergetics, and AD demonstrating that cannabinoid drugs might be a promising therapeutic approach for AD.
Funding: This work was supported by a funded project from the Agencia Estatal de Investigación-FEDER (RTI2018-093667-A-100) and the IBRO Return Home Fellowships 2019 received by Arnau Busquets-Garcia.
