Publications by authors named "Bindoff L"
Article Synopsis
- Mitochondrial diseases cause neuronal death and depletion of mitochondrial DNA (mtDNA), with astrocytes potentially playing a damaging role in neurodegeneration.
- Research using induced pluripotent stem cells (iPSCs) from patients with POLG mutations showed that the resulting astrocytes experienced significant mitochondrial dysfunction and developed a toxic phenotype.
- When these dysfunctioning astrocytes interacted with neurons, they induced neuronal death, highlighting a novel toxic contribution of astrocytes to the progression of POLG-related diseases.
Objective: To investigate the prevalence and natural history of POLG disease in the Norwegian population.
Methods: A national, population-based, retrospective study using demographic, clinical, and genetic data of patients with genetically confirmed POLG disease. The patients were diagnosed between 2002 and 2022, and were included into the Norwegian POLG Patient Registry.
We aimed to provide a detailed phenotypic description of status epilepticus (SE) in a large cohort of patients with POLG disease and identify prognostic biomarkers to improve the management of this life-threatening condition. In a multinational, retrospective study with data on patients with POLG disease from seven European countries, we identified those who had SE. The age of SE onset, accompanying clinical, laboratory, imaging and genetic findings were analysed.
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- A 3D brain organoid model is created to investigate POLG-related encephalopathy, a mitochondrial disease caused by POLG mutations, using patient-derived induced pluripotent stem cells (iPSCs).
- The generated cortical organoids display key disease features like abnormal structure, neuron loss, and depleted mitochondrial DNA, along with changes in critical neuronal development pathways and increased NOTCH and JAK-STAT signaling.
- Metformin treatment improved several issues found in the organoids, but did not resolve problems with inhibitory dopamine-glutamate neurons, making this model a useful tool for studying POLG disorders and related diseases linked to mitochondrial dysfunction.
Purpose: Pyridoxine-dependent epilepsy due to variants (PDE-ALDH7A1) is a rare disorder, presenting typically with severe neonatal, epileptic encephalopathy. Early diagnosis is imperative to prevent uncontrolled seizures. We have explored the role of EEG in the diagnosis and management of PDE.
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- Alpers' syndrome is a severe neurodegenerative disorder often caused by mutations in the POLG gene, leading to issues like intractable epilepsy and developmental regression, with no current effective treatments.
- Researchers created patient-specific induced pluripotent stem cells (iPSCs) from an Alpers' patient to study neural dysfunction and observed that organoids replicated key molecular changes seen in actual patient brain tissue.
- The study found that the NAD precursor nicotinamide riboside (NR) improved mitochondrial function, suggesting it could be a potential treatment for Alpers' syndrome and other similar mitochondrial disorders.*
Aberrant cholesterol metabolism causes neurological disease and neurodegeneration, and mitochondria have been linked to perturbed cholesterol homeostasis via the study of pathological mutations in the ATAD3 gene cluster. However, whether the cholesterol changes were compensatory or contributory to the disorder was unclear, and the effects on cell membranes and the wider cell were also unknown. Using patient-derived cells, we show that cholesterol perturbation is a conserved feature of pathological ATAD3 variants that is accompanied by an expanded lysosome population containing membrane whorls characteristic of lysosomal storage diseases.
View Article and Find Full Text PDFMit.OnOff: A Science Communication Project for Public Awareness about Mitochondrial Cytopathies.
Endocr Metab Immune Disord Drug Targets
September 2023
Introduction: Mitochondrial diseases are rare, heterogeneous, incurable and complex to diagnose. Probably due to their rareness, there is still a lack of literacy in this area, especially in society, but also in schools and in general, health care services. Accordingly, tools that may bring advancement in science and health literacy are needed.
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- * Researchers have developed a flow cytometry method to analyze multiple mitochondrial characteristics in brain organoids created from human induced pluripotent stem cells (iPSCs).
- * The provided protocol allows for efficient generation and analysis of cortical organoids, enabling the assessment of key mitochondrial proteins and the indirect measurement of mitochondrial DNA copy numbers within a few hours.
Article Synopsis
- Mutations in the POLG gene lead to mitochondrial diseases by disrupting the maintenance of mitochondrial DNA (mtDNA), yet effective treatments are lacking.
- The study examined neural stem cells derived from POLG patients and found that while mtDNA depletion occurred similarly in all cells, recovery was slower in cells with compound heterozygous mutations.
- Supplementing with deoxyribonucleosides (dNs) improved mtDNA recovery in patient cells, suggesting that dNs might be a promising therapeutic approach for mitochondrial diseases linked to POLG mutations.
Biallelic variants in are associated with a slowly progressive syndrome characterized by intellectual disability, spinocerebellar ataxia, cognitive decline and psychosis. The pitrilysin metallopeptidase 1 (PITRM1) is a mitochondrial matrix enzyme, which digests diverse oligopeptides, including the mitochondrial targeting sequences (MTS) that are cleaved from proteins imported across the inner mitochondrial membrane by the mitochondrial processing peptidase (MPP). Mitochondrial peptidases also play a role in the maturation of Frataxin, the protein affected in Friedreich's ataxia.
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- * Using an induced pluripotent stem cell (iPSC) model, researchers discovered that compound heterozygous neural stem cells (NSCs) showed greater mitochondrial dysfunction than homozygous NSCs, indicated by issues like reduced ATP production and increased levels of reactive oxygen species (ROS).
- * The study's findings highlight significant downregulation of key metabolic pathways in compound heterozygous NSCs, suggesting this iPSC model could aid in better understanding the relationship between genotypes and disease phenotypes in mitochondrial disorders, potentially
Background: Pyridoxine-dependent epilepsy (PDE) is a rare seizure disorder usually presenting with neonatal seizures. Most cases are caused by biallelic pathogenic ALDH7A1variants. While anti-seizure medications are ineffective, pyridoxine provides seizure control, and dietary interventions may be of benefit.
View Article and Find Full Text PDFWe aimed to investigate the epidemiology and natural history of FKRP-related limb-girdle muscular dystrophy R9 (LGMDR9) in Norway. We identified 153 genetically confirmed subjects making the overall prevalence 2.84/100,000, the highest reported figure worldwide.
View Article and Find Full Text PDFMusculoskeletal graft versus host disease (GVHD) is a rare manifestation of chronic GVHD (cGVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Left untreated, the disease can cause extensive damage to muscle tissue and joints. We describe a 62-year-old male with musculoskeletal GVHD and generalized muscle pain and stiffness.
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- Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) differ in origin, with ESCs coming from pre-implanted embryos and iPSCs being reprogrammed from somatic cells, but both are crucial for studying human neurological development.
- The research compares mitochondrial function and mitochondrial DNA (mtDNA) in ESCs and iPSCs across three developmental stages: pluripotent, neural progenitor, and astrocyte, revealing key differences in mitochondrial activity during differentiation.
- Findings indicate that while ESCs and iPSCs are similar at the pluripotent stage, iPSC-derived neural stem cells have lower ATP production than ESC-derived counterparts, whereas iPSC-derived astrocy
Mitochondrial disease is among the most commonly occurring metabolic disorders and is relevant for many medical specialties. This clinical review article discusses one of the most common mutations causing mitochondrial disease, namely m.3243A>G.
View Article and Find Full Text PDFAims: This study aimed to investigate associations between renal and extrarenal manifestations of mitochondrial diseases and their natural history as well as predictors of renal disease severity and overall disease outcome. The secondary aim was to generate a protocol of presymptomatic assessment and monitoring of renal function in patients with a defined mitochondrial disease.
Methods: A multicenter, retrospective cohort study was performed by the Mitochondrial Clinical and Research Network (MCRN).
Article Synopsis
- Mutations in mitochondrial genes result in significant alterations in mitochondrial functions, affecting neural stem cells (NSCs) and their differentiation into neurons and astrocytes.
- In research comparing POLG-mutated and control stem cells, it was found that while overall mitochondrial changes were similar, key processes like mtDNA replication and mitochondrial respiratory chain complex I did not function properly in the mutated cells.
- Specifically, the study noted that POLG mutations hindered the expected increases in mitochondrial membrane potential and ATP production during the differentiation of neuronal cells, while astrocyte differentiation remained unaffected, indicating a complex relationship between mutations and mitochondrial remodeling in early neural development.
Background: Large-scale mitochondrial DNA deletions (LMD) are a common genetic cause of mitochondrial disease and give rise to a wide range of clinical features. Lack of longitudinal data means the natural history remains unclear. This study was undertaken to describe the clinical spectrum in a large cohort of patients with paediatric disease onset.
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- * This report introduces a new flow cytometry method to analyze multiple mitochondrial characteristics in live and fixed human cells, including both stem cells and differentiated neural/glial cells.
- * The technique enables quantification of mitochondrial volume, membrane potential, and ROS levels, along with analyzing proteins related to the mitochondrial respiratory chain and DNA, all within a 2-3 hour time frame.
Article Synopsis
- The study focuses on the regulation of self-renewal and differentiation in stem cells, emphasizing the importance of mitochondrial remodeling and metabolic shifts between glycolysis and oxidative phosphorylation (OXPHOS) in maintaining stem cell properties.
- It suggests that the metabolic switch from glycolysis to OXPHOS is specific to different germ layers, with glycolysis remaining active in early ectoderm commitment, but decreasing when transitioning to mesoderm and endoderm lineages.
- The researchers found that while mitochondrial activity and ATP-linked respiration increase during the differentiation of human pluripotent stem cells into cardiac cells, mitochondrial content actually decreases, challenging the assumption that more OXPHOS activity corresponds with greater mitochondrial quantity.
Expanding the phenotypic spectrum of BCS1L-related mitochondrial disease.
Ann Clin Transl Neurol
November 2021
Objective: To delineate the full phenotypic spectrum of BCS1L-related disease, provide better understanding of the genotype-phenotype correlations and identify reliable prognostic disease markers.
Methods: We performed a retrospective multinational cohort study of previously unpublished patients followed in 15 centres from 10 countries. Patients with confirmed biallelic pathogenic BCS1L variants were considered eligible.
Article Synopsis
- - Mitophagy is crucial for removing damaged mitochondria to ensure proper brain function, and its impairment is linked to neurodegenerative diseases related to mutations.
- - In a study with astrocytes derived from iPSCs, researchers found gene downregulation related to mitophagy, confirming reduced autophagosome formation and various protein level changes under stress, all regulated by specific cellular pathways.
- - Treatment with nicotinamide riboside (NR) and metformin showed promise in correcting mitophagy defects and mitochondrial dysfunction in astrocytes with POLG mutations, highlighting potential therapies for these mitochondrial diseases.