scholarly journals Severe Form of ßIV-Spectrin Deficiency With Mitochondrial Dysfunction and Cardiomyopathy—A Case Report

2021 ◽  
Vol 12 ◽  
Author(s):  
Aziza Miriam Belkheir ◽  
Janine Reunert ◽  
Christiane Elpers ◽  
Lambert van den Heuvel ◽  
Richard Rodenburg ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Sodium Channels ◽  
Neuronal Degeneration ◽  
Severe Form ◽  
Neuronal Polarity ◽  
Developmental Arrest ◽  
Ankyrin G ◽  
Whole Exome ◽  
Stop Mutation ◽  
Cell Signaling Pathways

ßIV-spectrin is a protein of the spectrin family which is involved in the organization of the cytoskeleton structure and is found in high quantity in the axon initial segment and the nodes of Ranvier. Together with ankyrin G, ßIV-spectrin is responsible for the clustering of KCNQ2/3-potassium channels and NaV-sodium channels. Loss or reduction of ßIV-spectrin causes a destabilization of the cytoskeleton and an impairment in the generation of the action potential, which leads to neuronal degeneration. Furthermore, ßIV-spectrin has been described to play an important role in the maintenance of the neuronal polarity and of the diffusion barrier. ßIV-spectrin is also located in the heart where it takes an important part in the structural organization of ion channels and has also been described to participate in cell signaling pathways through binding of transcription factors. We describe two patients with a severe form of ßIV-spectrin deficiency. Whole-exome sequencing revealed the homozygous stop mutation c.6016C>T (p.R2006*) in the SPTBN4 gene. The phenotype of these patients is characterized by profound psychomotor developmental arrest, respiratory insufficiency and deafness. Additionally one of the patients presents with cardiomyopathy, optical nerve atrophy, and mitochondrial dysfunction. This is the first report of a severe form of ßIV-spectrin deficiency with hypertrophic cardiomyopathy and mitochondrial dysfunction.

scholarly journals Mitochondrial Dysfunction Induces Epigenetic Dysregulation by H3K27 Hyperacetylation to Perturb Active Enhancers in Parkinson’s Disease Models

2019 ◽  
Author(s):  
Minhong Huang ◽  
Dan Lou ◽  
Adhithiya Charli ◽  
Dehui Kong ◽  
Huajun Jin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Neuronal Degeneration ◽  
Ex Vivo ◽  
Genetic Mutation ◽  
Common Mechanism ◽  
Enhancer Activity ◽  
Active Enhancer ◽  
Environmental Component

AbstractGenetic mutations explain only 10-15% of cases of Parkinson’s disease (PD), while an overriding environmental component has been implicated in the etiopathogenesis of PD. But regardless of where the underlying triggers for the onset of familial and sporadic PD fall on the gene-environment axis, mitochondrial dysfunction emerges as a common mediator of dopaminergic neuronal degeneration. Herein, we employ a multidisciplinary approach to convincingly demonstrate that neurotoxicant exposure- and genetic mutation-driven mitochondrial dysfunction share a common mechanism of epigenetic dysregulation. Under both scenarios, lysine 27 acetylation of likely variant H3.2 (H3.2K27ac) increased in dopaminergic neuronal models of PD, thereby opening that region to active enhancer activity via H3K27 hyperacetylation. These vulnerable epigenomic loci represent potential transcription factor motifs for PD pathogenesis. We further confirmed the mitochondrial dysfunction induced H3K27ac during neurodegeneration in ex vivo models of PD. Our results reveal an exciting axis of ‘exposure/mutation-mitochondrial dysfunction-metabolism-H3K27ac-transcriptome’ for PD pathogenesis. Collectively, the novel mechanistic insights presented here interlinks mitochondrial dysfunction to epigenetic transcriptional regulation in dopaminergic degeneration as well as offer potential new epigenetic intervention strategies for PD.

scholarly journals Nodes of Ranvier and axon initial segments are ankyrin G–dependent domains that assemble by distinct mechanisms

2007 ◽  
Vol 177 (5) ◽  
pp. 857-870 ◽  
Author(s):  
Yulia Dzhashiashvili ◽  
Yanqing Zhang ◽  
Jolanta Galinska ◽  
Isabel Lam ◽  
Martin Grumet ◽  
...  
Keyword(s):  
Schwann Cells ◽  
Sodium Channels ◽  
Cytoskeletal Proteins ◽  
Action Potential Generation ◽  
Potential Generation ◽  
Nodes Of Ranvier ◽  
Ankyrin G ◽  
Sites Of Action ◽  
Axon Initial Segments ◽  
Inside Out

Axon initial segments (AISs) and nodes of Ranvier are sites of action potential generation and propagation, respectively. Both domains are enriched in sodium channels complexed with adhesion molecules (neurofascin [NF] 186 and NrCAM) and cytoskeletal proteins (ankyrin G and βIV spectrin). We show that the AIS and peripheral nervous system (PNS) nodes both require ankyrin G but assemble by distinct mechanisms. The AIS is intrinsically specified; it forms independent of NF186, which is targeted to this site via intracellular interactions that require ankyrin G. In contrast, NF186 is targeted to the node, and independently cleared from the internode, by interactions of its ectodomain with myelinating Schwann cells. NF186 is critical for and initiates PNS node assembly by recruiting ankyrin G, which is required for the localization of sodium channels and the entire nodal complex. Thus, initial segments assemble from the inside out driven by the intrinsic accumulation of ankyrin G, whereas PNS nodes assemble from the outside in, specified by Schwann cells, which direct the NF186-dependent recruitment of ankyrin G.

scholarly journals Mutant A53T α-Synuclein Induces Neuronal Death by Increasing Mitochondrial Autophagy

2011 ◽  
Vol 286 (12) ◽  
pp. 10814-10824 ◽  
Author(s):  
Vinay Choubey ◽  
Dzhamilja Safiulina ◽  
Annika Vaarmann ◽  
Michal Cagalinec ◽  
Przemyslaw Wareski ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Mitochondrial Dysfunction ◽  
Cortical Neurons ◽  
Neuronal Degeneration ◽  
Neuronal Cell Death ◽  
Lewy Bodies ◽  
Neuronal Cell ◽  
Dominant Negative ◽  
Contributing Factors ◽  
Mitofusin 2

Parkinson disease is characterized by the accumulation of aggregated α-synuclein as the major component of the Lewy bodies. α-Synuclein accumulation in turn leads to compensatory effects that may include the up-regulation of autophagy. Another common feature of Parkinson disease (PD) is mitochondrial dysfunction. Here, we provide evidence that the overactivation of autophagy may be a link that connects the intracellular accumulation of α-synuclein with mitochondrial dysfunction. We found that the activation of macroautophagy in primary cortical neurons that overexpress mutant A53T α-synuclein leads to massive mitochondrial destruction and loss, which is associated with a bioenergetic deficit and neuronal degeneration. No mitochondrial removal or net loss was observed when we suppressed the targeting of mitochondria to autophagosomes by silencing Parkin, overexpressing wild-type Mitofusin 2 and dominant negative Dynamin-related protein 1 or blocking autophagy by silencing autophagy-related genes. The inhibition of targeting mitochondria to autophagosomes or autophagy was also partially protective against mutant A53T α-synuclein-induced neuronal cell death. These data suggest that overactivated mitochondrial removal could be one of the contributing factors that leads to the mitochondrial loss observed in PD models.

scholarly journals A Review of Multiple Mitochondrial Dysfunction Syndromes, Syndromes Associated with Defective Fe-S Protein Maturation

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 989
Author(s):  
Elise Lebigot ◽  
Manuel Schiff ◽  
Marie-Pierre Golinelli-Cohen
Keyword(s):  
Mitochondrial Dysfunction ◽  
Acid Synthesis ◽  
Large Gene ◽  
Iron Sulfur ◽  
Whole Exome ◽  
Radiological Data ◽  
Cellular Pathways ◽  
Gene Panels ◽  
Generation Sequencing

Mitochondrial proteins carrying iron-sulfur (Fe-S) clusters are involved in essential cellular pathways such as oxidative phosphorylation, lipoic acid synthesis, and iron metabolism. NFU1, BOLA3, IBA57, ISCA2, and ISCA1 are involved in the last steps of the maturation of mitochondrial [4Fe-4S]-containing proteins. Since 2011, mutations in their genes leading to five multiple mitochondrial dysfunction syndromes (MMDS types 1 to 5) were reported. The aim of this systematic review is to describe all reported MMDS-patients. Their clinical, biological, and radiological data and associated genotype will be compared to each other. Despite certain specific clinical elements such as pulmonary hypertension or dilated cardiomyopathy in MMDS type 1 or 2, respectively, nearly all of the patients with MMDS presented with severe and early onset leukoencephalopathy. Diagnosis could be suggested by high lactate, pyruvate, and glycine levels in body fluids. Genetic analysis including large gene panels (Next Generation Sequencing) or whole exome sequencing is needed to confirm diagnosis.

scholarly journals In-frame deletion in canine PITRM1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration

2021 ◽  
Author(s):  
Marjo K Hytönen ◽  
Riika Sarviaho ◽  
Christopher B Jackson ◽  
Pernilla Syrjä ◽  
Tarja Jokinen ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Early Onset ◽  
Motor Coordination ◽  
Neuronal Degeneration ◽  
Amyloid Β ◽  
Homozygosity Mapping ◽  
Loss Of Function ◽  
Brain Disorder ◽  
Clinical Genetic ◽  
The Brain

Abstract We investigated the clinical, genetic, and pathological characteristics of a previously unknown severe juvenile brain disorder in several litters of Parson Russel Terriers. The disease started with epileptic seizures at 6 to 12 weeks of age and progressed rapidly to status epilepticus and death or euthanasia. Histopathological changes at autopsy were restricted to the brain. There was severe acute neuronal degeneration and necrosis diffusely affecting the grey matter throughout the brain with extensive intraneuronal mitochondrial crowding and accumulation of amyloid-β (Aβ). Combined homozygosity mapping and genome sequencing revealed an in-frame 6-bp deletion in the nuclear-encoded pitrilysin metallopeptidase 1 (PITRM1) encoding for a mitochondrial protease involved in mitochondrial targeting sequence processing and degradation. The 6-bp deletion results in the loss of two amino acid residues in the N-terminal part of PITRM1, potentially affecting protein folding and function. Assessment of the mitochondrial function in the affected brain tissue showed a significant deficiency in respiratory chain function. The functional consequences of the mutation were modeled in yeast and showed impaired growth in permissive conditions and an impaired respiration capacity. Loss-of-function variants in human PITRM1 result in a childhood-onset progressive amyloidotic neurological syndrome characterized by spinocerebellar ataxia with behavioral, psychiatric and cognitive abnormalities. Homozygous Pitrm1-knockout mice are embryonic lethal, while heterozygotes show a progressive, neurodegenerative phenotype characterized by impairment in motor coordination and Aβ deposits. Our study describes a novel early-onset PITRM1-related neurodegenerative canine brain disorder with mitochondrial dysfunction, Aβ accumulation, and lethal epilepsy. The findings highlight the essential role of PITRM1 in neuronal survival and strengthen the connection between mitochondrial dysfunction and neurodegeneration.

scholarly journals Fatty Acid-Binding Protein 3 is Critical for α-Synuclein Uptake and MPP+-Induced Mitochondrial Dysfunction in Cultured Dopaminergic Neurons

2019 ◽  
Vol 20 (21) ◽  
pp. 5358 ◽  
Author(s):  
Ichiro Kawahata ◽  
Luc Bousset ◽  
Ronald Melki ◽  
Kohji Fukunaga
Keyword(s):  
Fatty Acid ◽  
Mitochondrial Dysfunction ◽  
Dopaminergic Neurons ◽  
Fatty Acid Binding Protein ◽  
Neuronal Degeneration ◽  
Binding Protein ◽  
Mitochondrial Activity ◽  
Fatty Acid Binding ◽  
Acid Binding Protein

α-Synuclein is an abundant neuronal protein that accumulates in insoluble inclusions in Parkinson′s disease and other synucleinopathies. Fatty acids partially regulate α-Synuclein accumulation, and mesencephalic dopaminergic neurons highly express fatty acid-binding protein 3 (FABP3). We previously demonstrated that FABP3 knockout mice show decreased α-Synuclein oligomerization and neuronal degeneration of tyrosine hydroxylase (TH)-positive neurons in vivo. In this study, we newly investigated the importance of FABP3 in α-Synuclein uptake, 1-methyl-4-phenylpyridinium (MPP+)-induced axodendritic retraction, and mitochondrial dysfunction. To disclose the issues, we employed cultured mesencephalic neurons derived from wild type or FABP3−/− C57BL6 mice and performed immunocytochemical analysis. We demonstrated that TH+ neurons from FABP3+/+ mice take up α-Synuclein monomers while FABP3−/− TH+ neurons do not. The formation of filamentous α-Synuclein inclusions following treatment with MPP+ was observed only in FABP3+/+, and not in FABP3−/− neurons. Notably, detailed morphological analysis revealed that FABP−/− neurons did not exhibit MPP+-induced axodendritic retraction. Moreover, FABP3 was also critical for MPP+-induced reduction of mitochondrial activity and the production of reactive oxygen species. These data indicate that FABP3 is critical for α-Synuclein uptake in dopaminergic neurons, thereby preventing synucleinopathies, including Parkinson′s disease.

Probing the molecular mechanisms of neuronal degeneration: importance of mitochondrial dysfunction and calcineurin activation

2008 ◽  
Vol 22 (3) ◽  
pp. 253-262 ◽  
Author(s):  
Hiroyuki Uchino ◽  
Yasuhiro Kuroda ◽  
Saori Morota ◽  
Go Hirabayashi ◽  
Nagao Ishii ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Molecular Mechanisms ◽  
Neuronal Degeneration

scholarly journals Mitochondrial Dysfunction Contributes to Alveolar Developmental Arrest in Hyperoxia-Exposed Mice

2009 ◽  
Vol 40 (5) ◽  
pp. 511-518 ◽  
Author(s):  
Veniamin Ratner ◽  
Anatoly Starkov ◽  
Dzmitry Matsiukevich ◽  
Richard A. Polin ◽  
Vadim S. Ten
Keyword(s):  
Mitochondrial Dysfunction ◽  
Developmental Arrest

scholarly journals Mitochondrial- and Endoplasmic Reticulum-Associated Oxidative Stress in Alzheimer's Disease: From Pathogenesis to Biomarkers

2012 ◽  
Vol 2012 ◽  
pp. 1-23 ◽  
Author(s):  
E. Ferreiro ◽  
I. Baldeiras ◽  
I. L. Ferreira ◽  
R. O. Costa ◽  
A. C. Rego ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endoplasmic Reticulum ◽  
Mitochondrial Dysfunction ◽  
Neuronal Degeneration ◽  
Apoptotic Cell ◽  
Biological Fluids ◽  
Critical Role ◽  
Antioxidant Defenses

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, affecting several million of people worldwide. Pathological changes in the AD brain include the presence of amyloid plaques, neurofibrillary tangles, loss of neurons and synapses, and oxidative damage. These changes strongly associate with mitochondrial dysfunction and stress of the endoplasmic reticulum (ER). Mitochondrial dysfunction is intimately linked to the production of reactive oxygen species (ROS) and mitochondrial-driven apoptosis, which appear to be aggravated in the brain of AD patients. Concomitantly, mitochondria are closely associated with ER, and the deleterious crosstalk between both organelles has been shown to be involved in neuronal degeneration in AD. Stimuli that enhance expression of normal and/or folding-defective proteins activate an adaptive unfolded protein response (UPR) that, if unresolved, can cause apoptotic cell death. ER stress also induces the generation of ROS that, together with mitochondrial ROS and decreased activity of several antioxidant defenses, promotes chronic oxidative stress. In this paper we discuss the critical role of mitochondrial and ER dysfunction in oxidative injury in AD cellular and animal models, as well as in biological fluids from AD patients. Progress in developing peripheral and cerebrospinal fluid biomarkers related to oxidative stress will also be summarized.

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