Lorène Télot, Elodie Rousseau, Emmanuel Lesuisse, Camille Garcia, Bastien Morlet, Thibaut Léger, Jean-Michel Camadro, Valérie Serre, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Available online 9 January 2018, ISSN 0925-4439, doi:10.1016/j.bbadis.2018.01.010.
To better understand the biochemical sequelae of frataxin reduction, global protein expression analysis was performed using quantitative proteomic experiments in Friedreich's ataxia patient-derived B-lymphocytes as compared to controls. We were able to confirm a subset of changes in these cells and importantly, we observed previously unreported signatures of protein expression. Among the novel protein signatures that we have identified, the decrease in CHCHD4 might partly explain some aspects of the molecular pathogenesis of FRDA.
The identification of a core set of proteins changing in the FRDA pathogenesis is a useful tool in trying to decipher the function(s) of frataxin in order to clarify the mitochondrial metabolic disease process.
Wednesday, January 10, 2018
Effect Of Diazoxide on Friedreich Ataxia Models
Antonella Santoro, Sara Anjomani Virmouni, Eleonora Paradies, Valentina L Villalobos Coa, Sahar Al-Mahdawi, Mee Khoo, Vito Porcelli, Angelo Vozza, Mara Perrone, Nunzio Denora, Franco Taroni, Giuseppe Merla, Luigi Palmieri, Mark A Pook, Carlo M T Marobbio, Human Molecular Genetics, ddy016, doi:10.1093/hmg/ddy016
In this study, we tested diazoxide, a drug commonly used as vasodilator in the treatment of acute hypertension, on cellular and animal models of FRDA. We first showed that diazoxide increases frataxin protein levels in FRDA lymphoblastoid cell lines, via the mTOR pathway. We then explored the potential therapeutic effect of diazoxide in frataxin-deficient transgenic YG8sR mice and we found that prolonged oral administration of 3mpk/d diazoxide was found to be safe, but produced variable effects concerning efficacy. YG8sR mice showed improved beam walk coordination abilities and footprint stride patterns, but a generally reduced locomotor activity. Moreover, they showed significantly increased frataxin expression, improved aconitase activity and decreased protein oxidation in cerebellum and brain mitochondrial tissue extracts. Further studies are needed before this drug should be considered for FRDA clinical trials.
In this study, we tested diazoxide, a drug commonly used as vasodilator in the treatment of acute hypertension, on cellular and animal models of FRDA. We first showed that diazoxide increases frataxin protein levels in FRDA lymphoblastoid cell lines, via the mTOR pathway. We then explored the potential therapeutic effect of diazoxide in frataxin-deficient transgenic YG8sR mice and we found that prolonged oral administration of 3mpk/d diazoxide was found to be safe, but produced variable effects concerning efficacy. YG8sR mice showed improved beam walk coordination abilities and footprint stride patterns, but a generally reduced locomotor activity. Moreover, they showed significantly increased frataxin expression, improved aconitase activity and decreased protein oxidation in cerebellum and brain mitochondrial tissue extracts. Further studies are needed before this drug should be considered for FRDA clinical trials.
Sunday, January 7, 2018
Compounded medication for patients with rare diseases
Marc Dooms and Maria Carvalho; Orphanet Journal of Rare Diseases 201813:1 doi:10.1186/s13023-017-0741-y
When there is no authorized on- or in absence even no off-label treatment for patients with rare diseases, pharmacists have to compound medicinal products to meet the patients special needs. However it is important that there is evidence in the medical and/or pharmaceutical literature for such compounded medications.
When there is no on-label or even no off-label treatment for patients with rare diseases pharmacists have to compound the medication. This needs to be done in the best possible conditions by trained compounders following validates procedures.
In this way medicinal products of the best possible quality will be dispensed to our patients with rare diseases. “When it’s not in the book, it’s up to the cook”.
When there is no authorized on- or in absence even no off-label treatment for patients with rare diseases, pharmacists have to compound medicinal products to meet the patients special needs. However it is important that there is evidence in the medical and/or pharmaceutical literature for such compounded medications.
When there is no on-label or even no off-label treatment for patients with rare diseases pharmacists have to compound the medication. This needs to be done in the best possible conditions by trained compounders following validates procedures.
In this way medicinal products of the best possible quality will be dispensed to our patients with rare diseases. “When it’s not in the book, it’s up to the cook”.
Psychometric properties of outcome measures evaluating decline in gait in cerebellar ataxia: a systematic review
Sarah C. Milne, Anna Murphy, Nellie Georgiou-Kristian’s, Eppie M. Yiu, Martin B. Delatycki, Louise A. Corben; Gait & Posture, Available online 4 January 2018, ISSN 0966-6362, doi:10.1016/j.gaitpost.2017.12.031.
Cerebellar ataxia often results in impairment in ambulation secondary to gait pattern dysfunction and compensatory gait adjustments. Pharmaceutical and therapy-based interventions with potential benefit for gait in ataxia are starting to emerge, however evaluation of such interventions is hampered by the lack of outcome measures that are responsive, valid and reliable for measurement of gait decline in cerebellar ataxia.
Cerebellar ataxia often results in impairment in ambulation secondary to gait pattern dysfunction and compensatory gait adjustments. Pharmaceutical and therapy-based interventions with potential benefit for gait in ataxia are starting to emerge, however evaluation of such interventions is hampered by the lack of outcome measures that are responsive, valid and reliable for measurement of gait decline in cerebellar ataxia.
Pediatric Ataxia: Focus on Chronic Disordersca
David R Lynch, Ashley McCormick, Kimberly Schadt, Elizabeth Kichula, Seminars in Pediatric Neurology, Available online 5 January 2018, ISSN 1071-9091, doi:10.1016/j.spen.2018.01.001.
The differential diagnosis of ataxia remains challenging, and efficiently ascertaining the correct cause difficult. Modern genetic diagnostic techniques have provided many answers, but complete understanding of genetic results still requires basic knowledge of the clinical phenotypes. While few ataxias are treatable, the growth in research and clinical trials for the disorders like FRDA and AT suggest that a new era of treatments may soon be available. This will increase the need for precise yet cost-conscious diagnostic approaches.
The differential diagnosis of ataxia remains challenging, and efficiently ascertaining the correct cause difficult. Modern genetic diagnostic techniques have provided many answers, but complete understanding of genetic results still requires basic knowledge of the clinical phenotypes. While few ataxias are treatable, the growth in research and clinical trials for the disorders like FRDA and AT suggest that a new era of treatments may soon be available. This will increase the need for precise yet cost-conscious diagnostic approaches.
Sunday, December 31, 2017
A case-control spectral analysis of sleep in Friedreich's Ataxia
R. Forbes, S.S. Smith, A. Ritchie, J.D. O'Sullivan, S. Mantovani, Sleep Medicine, Volume 40, Supplement 1, December 2017, Page e209, ISSN 1389-9457, doi:10.1016/j.sleep.2017.11.611.
This study shows that power spectral alterations are present in FA patients when compared to healthy controls. This may have impli- cations for understanding the nature of sleep difficulties in FA, while their role in the progression of disease remains uncertain.
This study shows that power spectral alterations are present in FA patients when compared to healthy controls. This may have impli- cations for understanding the nature of sleep difficulties in FA, while their role in the progression of disease remains uncertain.
Emerging therapeutics for the treatment of Friedreich’s ataxia
Elisabetta Indelicato & Sylvia Bösch; Expert Opinion on Orphan Drugs Vol. 6 , Iss. 1,2018 doi:10.1080/21678707.2018.1409109
Despite the several trials finalized in the past years, no therapeutic is currently available for the treatment of FRDA. A number of promising compounds failed to show a significant effect when shifted in a randomized, placebo-controlled setting, because of missing natural history data, poor study design or insufficient preclinical evidence.
Despite the several trials finalized in the past years, no therapeutic is currently available for the treatment of FRDA. A number of promising compounds failed to show a significant effect when shifted in a randomized, placebo-controlled setting, because of missing natural history data, poor study design or insufficient preclinical evidence.
Why should neuroscientists worry about iron? The emerging role of ferroptosis in the pathophysiology of neuroprogressive diseases
Gerwyn Morris, Michael Berk, André F. Carvalho, Michael Maes, Adam J. Walker, Basant K. Puri, Behavioural Brain Research, Available online 28 December 2017, ISSN 0166-4328, doi:10.1016/j.bbr.2017.12.036.
Ferroptosis is a unique form of programmed death, characterised by cytosolic accumulation of iron, lipid hydroperoxides and their metabolites, and effected by the fatal peroxidation of polyunsaturated fatty acids in the plasma membrane. It is a major driver of cell death in neurodegenerative neurological diseases. Moreover, cascades underpinning ferroptosis could be active drivers of neuropathology in major psychiatric disorders. Oxidative and nitrosative stress can adversely affect mechanisms and proteins governing cellular iron homeostasis, such as the iron regulatory protein/iron response element system, and can ultimately be a source of abnormally high levels of iron and a source of lethal levels of lipid membrane peroxidation. Furthermore, neuroinflammation leads to the upregulation of divalent metal transporter-1 on the surface of astrocytes, microglia and neurones, making them highly sensitive to iron overload in the presence of high levels of non-transferrin-bound iron, thereby affording such levels a dominant role in respect of the induction of iron-mediated neuropathology. Mechanisms governing systemic and cellular iron homeostasis, and the related roles of ferritin and mitochondria are detailed, as are mechanisms explaining the negative regulation of ferroptosis by glutathione, glutathione peroxidase 4, the cysteine/glutamate antiporter system, heat shock protein 27 and nuclear factor erythroid 2-related factor 2. The potential role of DJ-1 inactivation in the precipitation of ferroptosis and the assessment of lipid peroxidation are described. Finally, a rational approach to therapy is considered, with a discussion on the roles of coenzyme Q10, iron chelation therapy, in the form of deferiprone, deferoxamine (desferrioxamine) and deferasirox, and N-acetylcysteine.
Ferroptosis is a unique form of programmed death, characterised by cytosolic accumulation of iron, lipid hydroperoxides and their metabolites, and effected by the fatal peroxidation of polyunsaturated fatty acids in the plasma membrane. It is a major driver of cell death in neurodegenerative neurological diseases. Moreover, cascades underpinning ferroptosis could be active drivers of neuropathology in major psychiatric disorders. Oxidative and nitrosative stress can adversely affect mechanisms and proteins governing cellular iron homeostasis, such as the iron regulatory protein/iron response element system, and can ultimately be a source of abnormally high levels of iron and a source of lethal levels of lipid membrane peroxidation. Furthermore, neuroinflammation leads to the upregulation of divalent metal transporter-1 on the surface of astrocytes, microglia and neurones, making them highly sensitive to iron overload in the presence of high levels of non-transferrin-bound iron, thereby affording such levels a dominant role in respect of the induction of iron-mediated neuropathology. Mechanisms governing systemic and cellular iron homeostasis, and the related roles of ferritin and mitochondria are detailed, as are mechanisms explaining the negative regulation of ferroptosis by glutathione, glutathione peroxidase 4, the cysteine/glutamate antiporter system, heat shock protein 27 and nuclear factor erythroid 2-related factor 2. The potential role of DJ-1 inactivation in the precipitation of ferroptosis and the assessment of lipid peroxidation are described. Finally, a rational approach to therapy is considered, with a discussion on the roles of coenzyme Q10, iron chelation therapy, in the form of deferiprone, deferoxamine (desferrioxamine) and deferasirox, and N-acetylcysteine.
Saturday, December 30, 2017
Association between iron related gene polymorphisms and Friedreich’s ataxia (FRDA) disease and peripheral neuropathy in Indian cohort
I. Singh, S. Shakya, R.K. Singh, A. Istaq, V. Goyal, S. Garima, A.K. Srivastava; Journal of the Neurological Sciences Volume 381, Supplement, 15 October 2017, Pages 895 Doi: 10.1016/j.jns.2017.08.2519
Till date, this is the largest study investigating HFE variations in FRDA. The observed over representation of p.H63D variation in FRDA and its correlation with the occurrence of peripheral neuropathy is intriguing in the context of dysregulated iron metabolism in FRDA due to loss of function mutations in FXN.
Till date, this is the largest study investigating HFE variations in FRDA. The observed over representation of p.H63D variation in FRDA and its correlation with the occurrence of peripheral neuropathy is intriguing in the context of dysregulated iron metabolism in FRDA due to loss of function mutations in FXN.
Transcriptional regulators of redox balance and other homeostatic processes with the potential to alter neurodegenerative disease trajectory.
Scott W. Burnside, Giles E. Hardingham; Biochemical Society Transactions Nov 17, 2017, 45 (6) 1295-1303; DOI: 10.1042/BST20170013
Diverse neurodegenerative diseases share some common aspects to their pathology, with many showing evidence of disruption to the brain's numerous homeostatic processes. As such, imbalanced inflammatory status, glutamate dyshomeostasis, hypometabolism and oxidative stress are implicated in many disorders. That these pathological processes can influence each other both up- and downstream makes for a complicated picture, but means that successfully targeting one area may have an effect on others. This targeting requires an understanding of the mechanisms by which homeostasis is maintained during health, in order to uncover strategies to boost homeostasis in disease. A case in point is redox homeostasis, maintained by antioxidant defences co-ordinately regulated by the transcription factor Nrf2, and capable of preventing not only oxidative stress but also inflammation and neuronal loss in neurodegenerative disease models. The emergence of other master regulators of homeostatic processes in the brain controlling inflammation, mitochondrial biogenesis, glutamate uptake and energy metabolism raises the question as to whether they too can be targeted to alter disease trajectory.
Diverse neurodegenerative diseases share some common aspects to their pathology, with many showing evidence of disruption to the brain's numerous homeostatic processes. As such, imbalanced inflammatory status, glutamate dyshomeostasis, hypometabolism and oxidative stress are implicated in many disorders. That these pathological processes can influence each other both up- and downstream makes for a complicated picture, but means that successfully targeting one area may have an effect on others. This targeting requires an understanding of the mechanisms by which homeostasis is maintained during health, in order to uncover strategies to boost homeostasis in disease. A case in point is redox homeostasis, maintained by antioxidant defences co-ordinately regulated by the transcription factor Nrf2, and capable of preventing not only oxidative stress but also inflammation and neuronal loss in neurodegenerative disease models. The emergence of other master regulators of homeostatic processes in the brain controlling inflammation, mitochondrial biogenesis, glutamate uptake and energy metabolism raises the question as to whether they too can be targeted to alter disease trajectory.
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