Jeremy D. Schmahmann, Neuroscience Letters, 2018, doi:10.1016/j.neulet.2018.07.005.
Structure function correlation studies following focal cerebellar lesions in adults and children permit a finer appreciation of the functional topography and nature of the cerebellar motor syndrome, cerebellar vestibular syndrome, and the third cornerstone of clinical ataxiology - the cerebellar cognitive affective syndrome. The ability to detect the cerebellar cognitive affective syndrome in real time in clinical neurology with a brief and validated scale should make it possible to develop a deeper understanding of the clinical consequences of cerebellar lesions in a wide range of neurological and neuropsychiatric disorders with a link to the cerebellum.
Monday, July 9, 2018
Sunday, July 8, 2018
Impact of Drosophila Models in the Study and Treatment of Friedreich’s Ataxia
Monnier, V.; Llorens, J.V.; Navarro, J.A., Int. J. Mol. Sci. 2018, 19, 1989.
Drosophila melanogaster has been for over a century the model of choice of several neurobiologists to decipher the formation and development of the nervous system as well as to mirror the pathophysiological conditions of many human neurodegenerative diseases. The rare disease Friedreich’s ataxia (FRDA) is not an exception. Since the isolation of the responsible gene more than two decades ago, the analysis of the fly orthologue has proven to be an excellent avenue to understand the development and progression of the disease, to unravel pivotal mechanisms underpinning the pathology and to identify genes and molecules that might well be either disease biomarkers or promising targets for therapeutic interventions. In this review, we aim to summarize the collection of findings provided by the Drosophila models but also to go one step beyond and propose the implications of these discoveries for the study and cure of this disorder. We will present the physiological, cellular and molecular phenotypes described in the fly, highlighting those that have given insight into the pathology and we will show how the ability of Drosophila to perform genetic and pharmacological screens has provided valuable information that is not easily within reach of other cellular or mammalian models.
Drosophila melanogaster has been for over a century the model of choice of several neurobiologists to decipher the formation and development of the nervous system as well as to mirror the pathophysiological conditions of many human neurodegenerative diseases. The rare disease Friedreich’s ataxia (FRDA) is not an exception. Since the isolation of the responsible gene more than two decades ago, the analysis of the fly orthologue has proven to be an excellent avenue to understand the development and progression of the disease, to unravel pivotal mechanisms underpinning the pathology and to identify genes and molecules that might well be either disease biomarkers or promising targets for therapeutic interventions. In this review, we aim to summarize the collection of findings provided by the Drosophila models but also to go one step beyond and propose the implications of these discoveries for the study and cure of this disorder. We will present the physiological, cellular and molecular phenotypes described in the fly, highlighting those that have given insight into the pathology and we will show how the ability of Drosophila to perform genetic and pharmacological screens has provided valuable information that is not easily within reach of other cellular or mammalian models.
Friday, July 6, 2018
Architectural Features of Human Mitochondrial Cysteine Desulfurase Complexes from Crosslinking Mass Spectrometry and Small-Angle X-Ray Scattering
Kai Cai, Ronnie O. Frederick, Hesam Dashti, John L. Markley; Structure, 2018, doi:10.1016/j.str.2018.05.017.
We present a structural model for the cysteine desulfurase-ISCU-frataxin complex derived from chemical crosslinking restraints in conjunction with the recent crystal structure of the cysteine desulfurase-ISCU-zinc complex and distance constraints from nuclear magnetic resonance.
We present a structural model for the cysteine desulfurase-ISCU-frataxin complex derived from chemical crosslinking restraints in conjunction with the recent crystal structure of the cysteine desulfurase-ISCU-zinc complex and distance constraints from nuclear magnetic resonance.
Targeting ERK signaling pathway by polyphenols as novel therapeutic strategy for neurodegeneration
Mohammad Hosein Farzaei, Devesh Tewari, Saeideh Momtaz, Sandro Argüelles, Seyed Mohammad Nabavi, Food and Chemical Toxicology, 2018, doi:10.1016/j.fct.2018.07.010.
Currently, there is remarkable interest in the beneficial effects of natural flavonoids to improve neural performance and prevent the onset and development of major neurodegenerative diseases. Natural products originated from medicinal plants, in particular antioxidants, have gained a great deal of attention due to their safe and non-toxic natures. Here, we summarized the effect of natural bioflavonoids on ERK signaling pathway and their molecular mechanism.
Currently, there is remarkable interest in the beneficial effects of natural flavonoids to improve neural performance and prevent the onset and development of major neurodegenerative diseases. Natural products originated from medicinal plants, in particular antioxidants, have gained a great deal of attention due to their safe and non-toxic natures. Here, we summarized the effect of natural bioflavonoids on ERK signaling pathway and their molecular mechanism.
Thursday, July 5, 2018
The Etiologies of Chronic Progressive Cerebellar Ataxia in a Korean Population
Kim JS, Kwon S, Ki CS, Youn J, Cho JW.; J Clin Neurol. 2018 Jul;14(3):374-380. Doi:10.3988/jcn.2018.14.3.374
Although the AR ataxias such as ataxia telangiectasia or FRDA are prevalent in most countries, they are extremely rare in the Korean population.26 In addition, genetic screening did not detect FRDA in the patients with undetermined ataxia. Therefore, routine screening of the FTX gene in the Korean population might not be needed unless patients show a clinical phenotype of FRDA.
FRDA is extremely rare, and to the best of our knowledge has never detected in the Korean population. In addition, phenotypes of patients in whom FRDA screening test was performed, did not correspond with FRDA.
Although the AR ataxias such as ataxia telangiectasia or FRDA are prevalent in most countries, they are extremely rare in the Korean population.26 In addition, genetic screening did not detect FRDA in the patients with undetermined ataxia. Therefore, routine screening of the FTX gene in the Korean population might not be needed unless patients show a clinical phenotype of FRDA.
FRDA is extremely rare, and to the best of our knowledge has never detected in the Korean population. In addition, phenotypes of patients in whom FRDA screening test was performed, did not correspond with FRDA.
Monday, July 2, 2018
Frataxin Restoration in the Nervous System: Possibilities for Gene Therapy
David R. Lynch, Elizabeth Kichula, and Hong Lin. Molecular Therapy, Available online 30 June 2018, ISSN 1525-0016, doi:10.1016/j.ymthe.2018.06.006
Many obstacles beyond those identified in the present study will appear in the translation of gene therapy from animal concept to human therapy. Still, the present work provides proof that gene therapy may be useful long term in FRDA, and hope for all those with this disorder.
Many obstacles beyond those identified in the present study will appear in the translation of gene therapy from animal concept to human therapy. Still, the present work provides proof that gene therapy may be useful long term in FRDA, and hope for all those with this disorder.
Friday, June 29, 2018
Structural characteristics of the central nervous system in Friedreich ataxia: an in vivo spinal cord and brain MRI study
Imis Dogan, Sandro Romanzetti, Claire Didszun, Shahram Mirzazade, Dagmar Timmann, Carsten Saft, Ludger Schöls, Matthis Synofzik, Ilaria A Giordano, Thomas Klockgether, Jörg B Schulz, Kathrin Reetz; Journal of Neurology, Neurosurgery & Psychiatry, June 2018 DOI:10.1136/jnnp-2018-318422
Neuropathological studies described reductions of dorsal root ganglia, the spinal cord at all levels and dentate nuclei.1 In vivo MRI approaches confirmed spinal cord alterations in FRDA, which were however focused on upper cervical cord areas,2 while quantitative measurements along the entire spinal cord length are lacking. We therefore aimed to investigate the morphometric pattern of the cervical and thoracic spinal cord in FRDA. In order to provide a more comprehensive picture of spinocerebellar-cerebral alterations, we additionally analysed anatomical brain MRI data and investigated the relative contribution of spinal and brain measurements for the prediction of clinical severity in FDRA.
Neuropathological studies described reductions of dorsal root ganglia, the spinal cord at all levels and dentate nuclei.1 In vivo MRI approaches confirmed spinal cord alterations in FRDA, which were however focused on upper cervical cord areas,2 while quantitative measurements along the entire spinal cord length are lacking. We therefore aimed to investigate the morphometric pattern of the cervical and thoracic spinal cord in FRDA. In order to provide a more comprehensive picture of spinocerebellar-cerebral alterations, we additionally analysed anatomical brain MRI data and investigated the relative contribution of spinal and brain measurements for the prediction of clinical severity in FDRA.
Wednesday, June 27, 2018
Friedreich Ataxia: Diagnostic Yield and Minimal Frequency in South Brazil
Helena Fussiger, Maria Luiza Saraiva-Pereira, Sandra Leistner-Segal, Laura Bannach Jardim. Cerebellum (2018). doi:10.1007/s12311-018-0958-x
Friedreich ataxia (FRDA) is an autosomal recessive disorder due to mutations in the FXN gene. FRDA is characterized by the classical triad of ataxia, absent reflexes, and Babinski sign, but atypical presentations might also occur. Our aims were to describe the proportion of FRDA diagnoses in suspected families living in Rio Grande do Sul, South Brazil, and to estimate a minimum frequency of symptomatic subjects. Subjects that were evaluated by molecular analysis for FRDA at the Hospital de Clínicas de Porto Alegre were identified in our files. Patients’ clinical manifestation and phenotypes were described and compared. The number of FRDA subjects alive in the last 5 years was determined. One hundred fifty-six index cases (families) were submitted to evaluation of GAA repeats at FXN since 1997: 27 were confirmed as FRDA patients. Therefore, the diagnostic yield was 17.3%. Proportion of classical, late onset, and retained reflexes subphenotypes were similar to those described by other studies. A minimum prevalence was estimated as 0.20:100.000 inhabitants. In conclusion, we verified that this FRDA population displayed the usual clinical characteristics, but with a lower period prevalence than those obtained in populations from Europe.
Friedreich ataxia (FRDA) is an autosomal recessive disorder due to mutations in the FXN gene. FRDA is characterized by the classical triad of ataxia, absent reflexes, and Babinski sign, but atypical presentations might also occur. Our aims were to describe the proportion of FRDA diagnoses in suspected families living in Rio Grande do Sul, South Brazil, and to estimate a minimum frequency of symptomatic subjects. Subjects that were evaluated by molecular analysis for FRDA at the Hospital de Clínicas de Porto Alegre were identified in our files. Patients’ clinical manifestation and phenotypes were described and compared. The number of FRDA subjects alive in the last 5 years was determined. One hundred fifty-six index cases (families) were submitted to evaluation of GAA repeats at FXN since 1997: 27 were confirmed as FRDA patients. Therefore, the diagnostic yield was 17.3%. Proportion of classical, late onset, and retained reflexes subphenotypes were similar to those described by other studies. A minimum prevalence was estimated as 0.20:100.000 inhabitants. In conclusion, we verified that this FRDA population displayed the usual clinical characteristics, but with a lower period prevalence than those obtained in populations from Europe.
Autonomic function testing in Friedreich’s ataxia
Elisabetta Indelicato, Alessandra Fanciulli, Jean-Pierre Ndayisaba, Wolfgang Nachbauer, Andreas Eigentler, Roberta Granata, Julia Wanschitz, Werner Poewe, Gregor K. Wenning, Sylvia Boesch. J Neurol (2018). Doi:10.1007/s00415-018-8946-0
FRDA patients may experience several autonomic symptoms and overall their burden correlates with disease severity. Nonetheless, clinical testing shows no major involvement of sudomotor and cardiovascular autonomic function.
FRDA patients may experience several autonomic symptoms and overall their burden correlates with disease severity. Nonetheless, clinical testing shows no major involvement of sudomotor and cardiovascular autonomic function.
Tuesday, June 26, 2018
Modeling Cardiac Dysfunction of Friedreich’s Ataxia Using Ventricular Sheets, Tissues and Chambers Engineered from Human Pluripotent Stem Cells
VANCOUVER, British Columbia, June 25, 2018 (GLOBE NEWSWIRE) -- Novoheart (“Novoheart” or the “Company”) (TSX-V:NVH) (FWB:3NH) is pleased to announce a presentation was delivered on June 22nd, 2018, entitled “Modeling Cardiac Dysfunction of Friedreich’s Ataxia Using Ventricular Sheets, Tissues and Chambers Engineered from Human Pluripotent Stem Cells,” at the Annual Meeting of the International Society for Stem Cell Research in Melbourne, Australia. The presentation includes data from research conducted with Pfizer Inc. on a 3D engineered human cardiac tissue disease model of Friedreich’s ataxia (FRDA), a neurodegenerative disease in which patients most often die of heart complications. The new disease model helps capture both electrical and mechanical defects of the heart observed in patients with FRDA.
FRDA is a hereditary, juvenile-onset neuro-muscular disease that afflicts over 1 in 50,000 people worldwide1, with symptoms including loss of muscular coordination and severe cardiac conditions. The latter, including heart failure and arrhythmias, is the main cause of death in FRDA patients2. Mouse models of FRDA have previously been created, but their non-human nature limits their application in drug development for human patients. As the first engineered 3D human cardiac tissue constructs of Friedreich’s ataxia, developed using Novoheart’s proprietary MyHeartTM Platform, the novel disease model captures key clinical symptoms seen in FRDA patients, including electrical and contractile dysfunction of the heart, thereby providing a highly effective human screening and discovery platform for developing novel therapeutics.
“We are very excited by the outcome of this study, and hope this will accelerate the development of safe and effective new therapies for FRDA patients. Also, by demonstrating the biomimetic capabilities of our MyHeartTM Platform for modeling diseased hearts, we are hoping to establish new standards for creating a proprietary library of disease models and expand our presence in drug discovery and precision medicine,” said Novoheart CSO, Dr. Kevin Costa.
FRDA is a hereditary, juvenile-onset neuro-muscular disease that afflicts over 1 in 50,000 people worldwide1, with symptoms including loss of muscular coordination and severe cardiac conditions. The latter, including heart failure and arrhythmias, is the main cause of death in FRDA patients2. Mouse models of FRDA have previously been created, but their non-human nature limits their application in drug development for human patients. As the first engineered 3D human cardiac tissue constructs of Friedreich’s ataxia, developed using Novoheart’s proprietary MyHeartTM Platform, the novel disease model captures key clinical symptoms seen in FRDA patients, including electrical and contractile dysfunction of the heart, thereby providing a highly effective human screening and discovery platform for developing novel therapeutics.
“We are very excited by the outcome of this study, and hope this will accelerate the development of safe and effective new therapies for FRDA patients. Also, by demonstrating the biomimetic capabilities of our MyHeartTM Platform for modeling diseased hearts, we are hoping to establish new standards for creating a proprietary library of disease models and expand our presence in drug discovery and precision medicine,” said Novoheart CSO, Dr. Kevin Costa.
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