Jiun-I Lai, Daniel Nachun, Lina Petrosyan, Benjamin Throesch, Erica Campau, Fuying Gao, Kristin K Baldwin, Giovanni Coppola, Joel M Gottesfeld, Elisabetta Soragni; bioRxiv 457093; doi: 10.1101/457093
We find that multiple cellular pathways are commonly affected by the loss of frataxin in CNS and peripheral nervous system neurons and these changes are partially restored by HDACi treatment.
Wednesday, October 31, 2018
Emerging Regulatory Role of Nrf2 in Iron, Heme, and Hemoglobin Metabolism in Physiology and Disease.
Kasai Shuya, Mimura Junsei, Ozaki Taku, Itoh Ken. Frontiers in Veterinary Science 5,242 2018 DOI=10.3389/fvets.2018.00242
In this review article, we describe and discuss the roles of Nrf2 in various iron-mediated bioreactions and its possible coevolution with iron and oxygen. Nrf2 regulates a wide range of cytoprotective responses and protects cells against various diseases and toxicities. In this review, we will focus on the Nrf2-mediated cytoprotective response achieved by iron regulation and detoxification.
In this review article, we describe and discuss the roles of Nrf2 in various iron-mediated bioreactions and its possible coevolution with iron and oxygen. Nrf2 regulates a wide range of cytoprotective responses and protects cells against various diseases and toxicities. In this review, we will focus on the Nrf2-mediated cytoprotective response achieved by iron regulation and detoxification.
Tuesday, October 30, 2018
Patients in research: still many roadblocks
Roos Eric C. BMJ 2018; 363 :k4387 doi:10.1136/bmj.k4387
Patient involvement is receiving increasing support as it can improve speed and quality of projects. At the same time, there is still significant resistance against it among doctors, investigators, and project managers. This “mental roadblock” must be fully removed to get the projected benefits.
Patient involvement is receiving increasing support as it can improve speed and quality of projects. At the same time, there is still significant resistance against it among doctors, investigators, and project managers. This “mental roadblock” must be fully removed to get the projected benefits.
Full partnership with patients is essential to any modern research enterprise
Wicks Paul, Richards Tessa, Denegri Simon, Godlee Fiona. Patients’ roles and rights in research BMJ 2018; 362 :k3193 doi:10.1136/bmj.k3193
Patient and public involvement in research is becoming a mainstream activity thanks to recognition by everyone in the research process from funders and regulators to conference organisers and publishers that it helps them do a better job.
Including patients and the public as partners in research is accepted best practice in several Western countries, and some funders make it mandatory.
Patient and public involvement in research is becoming a mainstream activity thanks to recognition by everyone in the research process from funders and regulators to conference organisers and publishers that it helps them do a better job.
Including patients and the public as partners in research is accepted best practice in several Western countries, and some funders make it mandatory.
Patients’ roles and rights in research- Patients in research: one step in a long path
Wicks P, Richards T, Denegri S, Godlee F. BMJ 2018;362:k3193. 10.1136/bmj.k3193 30045909
We need to engage patients with mobility, or other, limitations due to their disease. These are the patients that clinical research is working to help, so their inclusion is vital.
We need to engage patients with mobility, or other, limitations due to their disease. These are the patients that clinical research is working to help, so their inclusion is vital.
Unraveling the Role of Heme in Neurodegeneration
Chiabrando Deborah, Fiorito Veronica, Petrillo Sara, Tolosano Emanuela. Frontiers in Neuroscience 12 (2018) 712 DOI=10.3389/fnins.2018.00712
Heme (iron-protoporphyrin IX) is an essential co-factor involved in several biological processes, including neuronal survival and differentiation. Conversely, an excess of free-heme promotes oxidative stress and lipid peroxidation thus leading to cell death. The toxic properties of heme in the brain have been extensively studied during intracerebral or subarachnoid haemorrhages. Recently, a growing number of neurodegenerative disorders have been associated to alterations of heme metabolism. Hence, the etiology of such diseases remains undefined. The aim of this review is to highlight the neuropathological role of heme and to discuss the major heme-regulated pathways that might be crucial for the survival of neuronal cells. The understanding of the molecular mechanisms linking heme to neurodegeneration will be important for therapeutic purposes.
Heme (iron-protoporphyrin IX) is an essential co-factor involved in several biological processes, including neuronal survival and differentiation. Conversely, an excess of free-heme promotes oxidative stress and lipid peroxidation thus leading to cell death. The toxic properties of heme in the brain have been extensively studied during intracerebral or subarachnoid haemorrhages. Recently, a growing number of neurodegenerative disorders have been associated to alterations of heme metabolism. Hence, the etiology of such diseases remains undefined. The aim of this review is to highlight the neuropathological role of heme and to discuss the major heme-regulated pathways that might be crucial for the survival of neuronal cells. The understanding of the molecular mechanisms linking heme to neurodegeneration will be important for therapeutic purposes.
Monday, October 29, 2018
The impact of histone post-translational modifications in neurodegenerative diseases
Samantha N. Cobos, Seth A. Bennett, Mariana P. Torrente, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2018, ISSN 0925-4439, doi:10.1016/j.bbadis.2018.10.019.
Several histone PTMs have been associated with FRDA. One of the main causes of FRDA is the triplet repeat expansion GAA responsible for the transcriptional silencing of the FXN gene. Lymphoid cell lines from FRDA patients revealed that H3K4me2 and H3K4me marks decreased in the area surrounding the triplet repeat expansion when compared to unaffected cells. Moreover, both human tissues and a transgenic mice model showed an overall decrease in H3K9ac levels accompanied by increases in H3K9me2 and H3K9me3 levels. Collectively, these changes in histone marks would lead to lowered transcription, strongly suggesting that this is part of the mechanism that defines FRDA pathology.
In FRDA, treatment with nicotinamide (vitamin B3), an HDAC inhibitor, resulted in upregulation of the FXN gene by way of decreasing H3K9me3 and H3K27me3 at the FXN gene, and consequently increasing histone acetylation in both H3 and H4. This revels a possible treatment for FRDA, especially when considering the widespread availability, tolerability and affordability of vitamin B3.
Several histone PTMs have been associated with FRDA. One of the main causes of FRDA is the triplet repeat expansion GAA responsible for the transcriptional silencing of the FXN gene. Lymphoid cell lines from FRDA patients revealed that H3K4me2 and H3K4me marks decreased in the area surrounding the triplet repeat expansion when compared to unaffected cells. Moreover, both human tissues and a transgenic mice model showed an overall decrease in H3K9ac levels accompanied by increases in H3K9me2 and H3K9me3 levels. Collectively, these changes in histone marks would lead to lowered transcription, strongly suggesting that this is part of the mechanism that defines FRDA pathology.
In FRDA, treatment with nicotinamide (vitamin B3), an HDAC inhibitor, resulted in upregulation of the FXN gene by way of decreasing H3K9me3 and H3K27me3 at the FXN gene, and consequently increasing histone acetylation in both H3 and H4. This revels a possible treatment for FRDA, especially when considering the widespread availability, tolerability and affordability of vitamin B3.
Non-invasive Focal Mechanical Vibrations Delivered by Wearable Devices: An Open-Label Pilot Study in Childhood Ataxia
Schirinzi, T., Romano, A., Favetta, M., Sancesario, A., Burattini, R., Summa, S., Della Bella, G., Castelli, E., Bertini, E., Petrarca, M., … Vasco, G. (2018). Frontiers in neurology, 9, 849. doi:10.3389/fneur.2018.00849
Non-invasive focal mechanical vibrations (NIFMV) now represent a strategy of increasing interest to improve motor control in different neurological diseases. Nanotechnology allowed the creation of wearable devices transforming thermal variations into mechanical energy with focal vibrations. This kind of wearable stimulators (WS) has produced encouraging preliminary results when used in the treatment of movement disorders and ataxia in adults. In this open label pilot study we first evaluated the feasibility, safety and effectiveness of NIFMV by WS in a cohort of 10 patients with childhood ataxia, a phenomenological category including different conditions still lacking of effective symptomatic therapies. Through the assessment of both clinical rating scales and spatio-temporal gait parameters via standardized gait analysis, we observed that a 4 weeks long treatment with WS Equistasi® was safe and provided significantly different effects in stride features of patients with slow/non-progressive cerebellar ataxia and Friedreich's Ataxia.
Non-invasive focal mechanical vibrations (NIFMV) now represent a strategy of increasing interest to improve motor control in different neurological diseases. Nanotechnology allowed the creation of wearable devices transforming thermal variations into mechanical energy with focal vibrations. This kind of wearable stimulators (WS) has produced encouraging preliminary results when used in the treatment of movement disorders and ataxia in adults. In this open label pilot study we first evaluated the feasibility, safety and effectiveness of NIFMV by WS in a cohort of 10 patients with childhood ataxia, a phenomenological category including different conditions still lacking of effective symptomatic therapies. Through the assessment of both clinical rating scales and spatio-temporal gait parameters via standardized gait analysis, we observed that a 4 weeks long treatment with WS Equistasi® was safe and provided significantly different effects in stride features of patients with slow/non-progressive cerebellar ataxia and Friedreich's Ataxia.
A case series of hereditary cerebellar ataxias in a highly consanguineous population from Northeast Brazil
Deborah Moreira Rangel, Paulo Ribeiro Nóbrega, Maria Luiza Saraiva-Pereira, Laura Bannach Jardim, Pedro Braga-Neto, Parkinsonism & Related Disorders, 2018, ISSN 1353-8020, doi:10.1016/j.parkreldis.2018.10.027.
A total of 47 patients had ataxia as the main symptom. A high prevalence of consanguinity was found in the population studied (40.4%); The most prevalent diseases were: Friedreich's ataxia in 35% (n = 7), Niemann-Pick type C (NPC) in 15% (n = 3), and ataxia with oculomotor apraxia type 2 in 15% (n = 3).
In contrast with other studies, our prevalence of recessive ataxias was much higher than that of dominant ataxias. These findings might be explained by the high number of patients living in rural areas with a higher rate of consanguineous marriages, absence of a dominant ataxia founder effect or difficult access to healthcare system.
A total of 47 patients had ataxia as the main symptom. A high prevalence of consanguinity was found in the population studied (40.4%); The most prevalent diseases were: Friedreich's ataxia in 35% (n = 7), Niemann-Pick type C (NPC) in 15% (n = 3), and ataxia with oculomotor apraxia type 2 in 15% (n = 3).
In contrast with other studies, our prevalence of recessive ataxias was much higher than that of dominant ataxias. These findings might be explained by the high number of patients living in rural areas with a higher rate of consanguineous marriages, absence of a dominant ataxia founder effect or difficult access to healthcare system.
Saturday, October 27, 2018
Intraepidermal Nerve Fiber Density in Friedreich’s Ataxia
Elisabetta Indelicato, Wolfgang Nachbauer, Andreas Eigentler, Dagmar Rudzki, Julia Wanschitz, Sylvia Boesch; Journal of Neuropathology & Experimental Neurology, , nly100, doi:10.1093/jnen/nly100
In the present study, we aimed at gaining further insight in the PNS involvement in FRDA by investigating small nerve fibers in vivo. For this purpose, we evaluated the intraepidermal nerve fiber (IENF) density in skin-biopsies of the lower leg and applied clinical assessments of small fiber function (painDETECT, quantitative sensory testing) in 17 FRDAs.
In the present study, we aimed at gaining further insight in the PNS involvement in FRDA by investigating small nerve fibers in vivo. For this purpose, we evaluated the intraepidermal nerve fiber (IENF) density in skin-biopsies of the lower leg and applied clinical assessments of small fiber function (painDETECT, quantitative sensory testing) in 17 FRDAs.
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