Mitochondria in the nervous system: From Health to disease, part II

Maria Teresa Carrì, Brian M. Polster, Philip M. Beart, Mitochondria in the nervous system: From Health to disease, part II, Neurochemistry International, Available online 10 April 2018, ISSN 0197-0186, doi:10.1016/j.neuint.2018.04.006.

In Part II of this Special Issue on "Mitochondria in the Nervous System: From Health to Disease", the editors bring together more reviews and original articles from researchers in the field of mitochondrial metabolism in the healthy and diseased nervous system. Subjects span from basic mitochondrial physiology to papers on mitochondrial dynamics and to those altered states of the nervous system that can be considered “mitopathologies”. Finally, a few papers approach aspects of mitochondrial biology linked to the feasibility and validity of a mitochondrial therapy.

The fact that lack of a single protein affects all of these processes supports the concept that they are all interconnected, albeit it is difficult to pinpoint the “primum movens” in the chain of events leading to neurodegeneration. Furthermore, Friedreich's ataxia is another example of a disease where mutations in a gene coding for a ubiquitously expressed protein mostly affect a specific tissue or cell type.

Caso práctico enfermería: Intento de autolisis en Ataxia de Friedreich

Rocío del Carmen Ortiz Gutiérrez; Laura Quintana Pérez; María Romero Palomar; Revista Médica Electrónica PortalesMedicos.com, 10 abril, 2018


Con un plan de cuidados de enfermería, junto con el trabajo del resto de profesionales del equipo multidisciplinar, el ingreso en la unidad de agudos de la paciente ha resultado satisfactoria, en cuanto al afrontamiento de su patología crónica.
No obstante, se derivará a la unidad de salud mental de su centro de atención primaria, para posterior seguimiento. Se aconseja a su vez la asistencia a asociaciones de afectados de Ataxia de Friedreich para socialización con pacientes de igual a igual.

Silent pauses in aphasia

Georgia Angelopoulou, Dimitrios Kasselimis, George Makrydakis, Maria Varkanitsa, Petros Roussos, Dionysis Goutsos, Ioannis Evdokimidis, Constantin Potagas, Neuropsychologia, Available online 7 April 2018, ISSN 0028-3932, doi:10.1016/j.neuropsychologia.2018.04.006.

Several studies have demonstrated that pausing may be affected by neurological conditions. Individuals with amyotrophic lateral sclerosis and Friedreich’s Ataxia have been shown to produce longer pauses in conversational speech compared to controls. These studies clearly show prominent differences in pausing between healthy participants and pathological populations. These studies have also demonstrated how pausing measures may be used as diagnostic markers and/or as markers of cognitive changes over time. Taken together, these findings suggest that pauses could be an integral aspect of cognitive assessment in clinical practice and research.

Randomized, clinical trial of RT001: Early signals of efficacy in Friedreich's ataxia

Theresa Zesiewicz MD, FAAN, Frederic Heerinckx MPharm, Robert De Jager MD, FACP, Omid Omidvar MD, Marcus Kilpatrick PhD, Jessica Shaw MPH, Mikhail S. Shchepinov PhD, Movement Disorders : Official Journal of the Movement Disorder Society, First published: 6 April 2018 doi:10.1002/mds.27353

RT001 was found to be safe and tolerable over 28 days, and improved peak workload. Further research into the effect of RT001 in Friedreich's ataxia is warranted.

Strong correlations among four measures of disease progression in Friedreich's ataxia

Harry J. Saal PhD, Frederic Heerinckx, Rezi Zawadzki DrPH, Omid Omidvar MD, Marcus Kilpatrick PhD, Theresa Zesiewicz MD, Movement Disorders : Official Journal of the Movement Disorder Society [06 Apr 2018] Letter DOI: 10.1002/mds.27351

Using the data from a double-blind, placebo-controlled trial in 19 FRDA patients testing RT001 a linoleic acid derivative, baseline FARS-Neuro scores were compared with T25FW and CPET to measure peak workload/kg and peak oxygen consumption.

Drosophila melanogaster Models of Friedreich’s Ataxia

P. Calap-Quintana, J. A. Navarro, J. González-Fernández, M. J. Martínez-Sebastián, M. D. Moltó, and J. V. Llorens, BioMed Research International, vol. 2018, Article ID 5065190, 20 pages, 2018. doi:10.1155/2018/5065190

FXN is evolutionarily conserved, with orthologs in essentially all eukaryotes and some prokaryotes, leading to the development of experimental models of this disease in different organisms. These FRDA models have contributed substantially to our current knowledge of frataxin function and the pathogenesis of the disease, as well as to explorations of suitable treatments. Drosophila melanogaster, an organism that is easy to manipulate genetically, has also become important in FRDA research. This review describes the substantial contribution of Drosophila to FRDA research since the characterization of the fly frataxin ortholog more than 15 years ago. Fly models have provided a comprehensive characterization of the defects associated with frataxin deficiency and have revealed genetic modifiers of disease phenotypes. In addition, these models are now being used in the search for potential therapeutic compounds for the treatment of this severe and still incurable disease.

Clinical and genetic aspects of defects in the mitochondrial iron–sulfur cluster synthesis pathway

Vanlander, A.V. & Van Coster, R. J Biol Inorg Chem (2018). doi:10.1007/s00775-018-1550-z

Iron–sulfur clusters are evolutionarily conserved biological structures which play an important role as cofactor for multiple enzymes in eukaryotic cells. The biosynthesis pathways of the iron–sulfur clusters are located in the mitochondria and in the cytosol. The mitochondrial iron–sulfur cluster biosynthesis pathway (ISC) can be divided into at least twenty enzymatic steps. Since the description of frataxin deficiency as the cause of Friedreich’s ataxia, multiple other deficiencies in ISC biosynthesis pathway have been reported. In this paper, an overview is given of the clinical, biochemical and genetic aspects reported in humans affected by a defect in iron–sulfur cluster biosynthesis.

Brain mitochondrial iron accumulates in Huntington's disease, mediates mitochondrial dysfunction, and can be removed pharmacologically

Sonal Agrawal, Julia Fox, Baskaran Thyagarajan, Jonathan Fox, Free Radical Biology and Medicine, Available online 4 April 2018, ISSN 0891-5849, doi:10.1016/j.freeradbiomed.2018.04.002.

We demonstrate here that human Huntington's disease and mouse model HD (12-week R6/2 and 12-month YAC128) brains accumulated mitochondrial iron and showed increased expression of iron uptake protein mitoferrin 2 and decreased iron-sulfur cluster synthesis protein frataxin.

Friedreich Ataxia Scientific News: Monthly update: March 8- April 5, 2018

Monthly update: March 8- April 5, 2018 The transcriptional regulator CCCTC-binding factor limits oxidative stress in endothelial cells Suggest a potential mechanism for endothelial dysfunction in FRDA. Read more »

Idebenone: Novel Strategies to Improve Its Systemic and Local Efficacy Liposomes, cyclodextrins and lipid-based nanoparticles could open new perspectives in the therapeutic outcomes of this strong antioxidant agent. Read more »

Impact of Mobility Device Use on Quality of Life in Children With Friedreich Ataxia Mobility device use is associated with significant worsening of all domains of quality of life in children with Friedreich ataxia. Read more »

Management of Pediatric Movement Disorders: Present and Future Treatment such as gene therapy, epigenetic modulation, and stem cell therapy hold promise for improving outcomes in both primary and secondary causes of movement disorders. Read more »

Structure and mechanism of mitochondrial electron transport chain This work provided solid evidence for the existence of megacomplex of human respirasome. This is a great step forward into conquering many severe neurodegenerative diseases, including Alzheimer's syndrome, Parkinson's disease, multiple sclerosis, friedreich's ataxia, Amyotrophic lateral sclerosis, etc. Read more »

Dysfunction in the mitochondrial Fe-S assembly machinery leads to formation of the chemoresistant truncated VDAC1 isoform without HIF-1α activation We show that hypoxia promotes the downregulation of several proteins (ISCU, NFS1, FXN) involved in the early steps of mitochondrial Fe-S cluster biogenesis. Read more »

Rapid exhaustion of auditory neural conduction in a prototypical mitochondrial disease, Friedreich ataxia A large decrease in conduction velocity along auditory neurons occurs within seconds, attributed to fast energetic failure. Read more »

Cell Therapy Instigates Neural Repair In Friedreich’s Ataxia Mice Transplantation of bone marrow cells that express frataxin into the FRDA mice caused the upregulation of frataxin as well as a number of antioxidative proteins, as well as improving movement and coordination in the mice. Read more »

Assistance circulatoire et transplantation d’organes thoraciques chez l’enfant Les maladies neuro-dégénératives (Friedreich, Duchenne) ou certaines maladies mitochondriales, ainsi que des séquelles graves d'accident vasculaire cérébral, sont considérées comme des contre-indications à la greffe. Read more »

Caractéristiques cliniques ; électrophysiologiques et évolutives des formes atypiques de l’ataxie héréditaire de Friedreich : à propos sept cas Devant un tableau d’ataxie atypique avec un début tardif et des réflexes vifs ou conservés l’ataxie de Freidreich doit être évoquée et une étude génétique doit être envisagée. Read more »

L’accumulation intracérébrale de fer, un aspect IRM atypique de l’ataxie de Friedreich L’AF devrait systématiquement être envisagée devant un syndrome cérébelleux lentement progressif même chez les sujets âgés et même en l’absence d’antécédent familial en cas de dépôt de fer au niveau du cervelet ou des noyaux gris centraux à l’IRM. Read more »

L’atteinte du système nerveux périphérique au cours des ataxies cérébelleuses héréditaires autosomiques récessives (ACAR) : étude de 33 cas Read more »

Étude de la population réunionnaise atteinte d’ataxie de Friedreich La Réunion possède un cluster d’ataxie de Friedreich à faible nombre de répétition GAA, dont les caractéristiques peuvent rappeler les formes acadiennes, qui sont également le résultat d’un effet fondateur. Read more »

Mitofusin-Dependent ER Stress Triggers Glial Dysfunction and Nervous System Degeneration in a Drosophila Model of Friedreich’s Ataxia Marf and ER stress represent a hub in the neurodegenerative process of FRDA and uncover both as important elements substantially involved the FRDA pathology. Read more »

Identification of p38 MAPK as a novel therapeutic target for Friedreich’s ataxia The involvement of the p38 MAPK pathway in the pathogenesis of FRDA and the potential use of p38 inhibitors as a treatment for FRDA. Read more »

Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood Biallelic mutations in PMPCB cause defects in MPP proteolytic activity leading to dysregulation of iron-sulfur cluster biogenesis and triggering a complex neurological phenotype of neurodegeneration in early childhood. Read more »

Iron regulatory protein deficiency compromises mitochondrial function in murine embryonic fibroblasts Overexpression of human ISCU and frataxin in Irp1 or Irp2-null cells was able to rescue the defects in iron-sulfur cluster biogenesis and mitochondrial quality. Read more »

Frataxin overexpression in Müller cells protects retinal ganglion cells in a mouse model of ischemia/reperfusion injury in vivo The aim of this study was to evaluate the effect of frataxin overexpression in Müller cells on neuronal survival after retinal ischemia/reperfusion in the mouse in vivo. Read more »

Genetic Infiltrative Cardiomyopathies Friedreich ataxia: cardiac dysfunction from congestive heart failure or arrhythmia accounts for an estimated 59% of death.  Read more »

Resting-state connectivity in neurodegenerative disorders: Is there potential for an imaging biomarker? For rare neurodegenerative diseases, no clear conclusions can be drawn due to the few published results.  Read more »

Optical coherence tomography in autosomal recessive spastic ataxia of Charlevoix-Saguenay This is a useful tool in identifying cases of autosomal recessive spastic ataxia of Charlevoix-Saguenay from other causes of ataxia. Read more »

Distinct effects of frataxin missence point mutations on mitochondrial localization, protein processing, and cellular metabolism These studies will examine the mechanism by which FRDA-associated missense mutations impair FXN processing and explore the influence they have on cellular metabolism, in addition to exploring the use of fatty acids as a potential therapeutic strategy. Read more »

Interactions of iron-bound frataxin with ISCU and ferredoxin on the cysteine desulfurase complex leading to Fe-S cluster assembly Our results show that FXN tightly binds a single Fe2+ but not Fe3+. While FXN (with or without bound Fe2+) does not bind the scaffold protein ISCU directly. Read more »

Biomarcadores epigenéticos: hacia su implantación en la rutina clínica / Epigenetic biomarkers: towards their incorporation into clinical routine En un futuro cercano, este tipo de tecnologías se incorporarán a los laboratorios clínicos y, por lo tanto, el uso de estos biomarcadores se implementará en la rutina de diagnóstico clínico, contribuyendo así a la aplicación real de la teragnosis y mejorando la medicina de precisión. Read more »

Large-scale computational drug repositioning to find treatments for rare diseases eMatchSite is combined with virtual screening to systematically explore opportunities to reposition known drugs to proteins associated with rare diseases. Read more »

The transcriptional regulator CCCTC-binding factor limits oxidative stress in endothelial cells

Anna R Roy, Abdalla Ahmed, Peter V DiStefano, Lijun Chi, Nadiya Khyzha, Niels Galjart, Michael D Wilson, Jason E Fish and Paul Delgado Olguin; J. Biol. Chem., First Published on April 2, 2018 doi: 10.1074/jbc.M117.814699

Ctcf promotes vascular development, and limits oxidative stress in endothelial cells. These results reveal a function for Ctcf in vascular development, and suggest a potential mechanism for endothelial dysfunction in FRDA.