Tuesday, May 8, 2018

Monthly update: April 6-Mai 6, 2018

Monthly update: April 6-Mai 6, 2018

Sunday, May 6, 2018

Saturday, May 5, 2018

Friday, May 4, 2018

Saturday, April 28, 2018

Thursday, April 26, 2018

Wednesday, April 25, 2018

Tuesday, April 24, 2018

Sunday, April 22, 2018

Sunday, April 22, 2018

Friday, April 20, 2018

Wednesday, April 18, 2018

Tuesday, April 17, 2018

Wednesday, April 11, 2018

Sunday, April 8, 2018

Saturday, April 7, 2018

Friday, April 6, 2018

Sunday, May 6, 2018

Low-level mitochondrial heteroplasmy modulates DNA replication, glucose metabolism and lifespan in mice

Misa Hirose, Paul Schilf, Yask Gupta, Kim Zarse, Axel Künstner, Anke Fähnrich, Hauke Busch, Junping Yin, Marvin N. Wright, Andreas Ziegler, Marie Vallier, Meriem Belheouane, John F Baines, Diethard Tautz, Kornelia Johann, Rebecca Oelkrug, Jens Mittag, Hendrik Lehnert, Alaa Othman, Olaf Jöhren, Markus Schwaninger, Cornelia Prehn, Jerzy Adamski, Kensuke Shima, Jan Rupp, Robert Häsler, Georg Fuellen, Rüdiger Köhling, Michael Ristow & Saleh M. Ibrahim; Scientific Reports volume 8, Article number: 5872 (2018) doi:10.1038/s41598-018-24290-6

One example of such disorders is Friedreich Ataxia (FA), which is resulted by the impaired expression of the nuclear genome encoded frataxin protein that affect OXPHOS function by mediating mitochondrial iron-sulphur-cluster biosynthesis. FA patients develop diabetes and exhibited decreased lifespan, and experimental evidence using different models showed that a frataxin knock-out cause diabetes in mice, and knocking down of the frataxin gene resulted in shorter lifespan in worms.

Advances in Biomarker-Guided Therapy for Pediatric- and Adult-Onset Neuroinflammatory Disorders: Targeting Chemokines/Cytokines

Michael R. Pranzatelli, Front Immunol. 2018; 9: 557. Published online 2018 Apr 4. doi:10.3389/fimmu.2018.00557

The concept and recognized components of “neuroinflammation” are expanding at the intersection of neurobiology and immunobiology. Chemokines (CKs), no longer merely necessary for immune cell trafficking and positioning, have multiple physiologic, developmental, and modulatory functionalities in the central nervous system (CNS) through neuron–glia interactions and other mechanisms affecting neurotransmission. They issue the “help me” cry of neurons and astrocytes in response to CNS injury, engaging invading lymphoid cells (T cells and B cells) and myeloid cells (dendritic cells, monocytes, and neutrophils) (adaptive immunity), as well as microglia and macrophages (innate immunity), in a cascade of events, some beneficial (reparative), others destructive (excitotoxic).
Filling in knowledge gaps between pediatric- and adult-onset neuroinflammation by systematic collection of CSF data on CKs/cytokines in temporal and clinical contexts and incorporating immunobiomarkers in clinical trials is a challenge hereby set forth for clinicians and researchers.
Interferon-gamma, the sole type 2 IFN, binds to the IFN-γ-R1 and IFN-γ-R2 receptors (also denoted IFNGR1 and R2). IFN-γ-1b is FDA-approved for chronic granulomatous diseases and osteopetrosis. A phase III study (NCT024155127) of IFN-γ-1b for the treatment of Friedreich ataxia has been completed recently, but without study results yet, based on positive results from as phase II study. Treatment with IFN-γ exacerbated MS.
In preclinical studies, administration of G-CSF in a murine model of Friedreich ataxia resulted in clinical improvement and reduction in inflammation and gliosis. IL-10 is such a powerful counteractant of pro-inflammatory cytokines, one would hope there is more progress in this area.

Saturday, May 5, 2018

Lipophilic methylene blue analogues enhance mitochondrial function and increase frataxin levels in a cellular model of Friedreich’s Ataxia

Omar M. Khdour, Indrajit Bandyopadhyay, Sandipan Roy Chowdhury, Nishant P. Visavadiya, Sidney M. Hecht, Bioorganic & Medicinal Chemistry, Available online 4 May 2018, ISSN 0968-0896, doi:10.1016/j.bmc.2018.05.005.

A series of methylene blue analogues has been synthesized and characterized for their in vitro biochemical and biological properties in cultured Friedreich’s ataxia lymphocytes. Favorable methylene blue analogues were shown to increase frataxin levels and mitochondrial biogenesis, and to improve aconitase activity. The analogues were found to be good ROS scavengers, and able to protect cultured FRDA lymphocytes from oxidative stress resulting from inhibition of complex I and from glutathione depletion. The analogues also preserved mitochondrial membrane potential and augmented ATP production.

How Orphan Drugs Became a Highly Profitable Industry

The Scientist; By Diana Kwon | May 1, 2018

Government incentives, advances in technology, and an army of patient advocates have spun a successful market—but abuses of the system and exorbitant prices could cause a backlash.

Friday, May 4, 2018

The mystery of the cerebellum: clues from experimental and clinical observations

Charlotte Lawrenson, Martin Bares, Anita Kamondi, Andrea Kovács, Bridget Lumb, Richard Apps, Pavel Filip and Mario Manto; Cerebellum & Ataxias 20185:8 doi:10.1186/s40673-018-0087-9

Its dense connectivity with cerebral cortex, thalamic nuclei, brainstem nuclei and spinal cord, as well as its critically high number of neurons put the cerebellum in a unique position for a participation in cognitive, affective and sensorimotor operations. This special session has highlighted this aspect by taking fear behaviour, motor control, timing contributions and tremor as 4 examples of productive fields of research.

Current and Promising Therapies in Autosomal Recessive Ataxias

Vincent Picher-Martel, Nicolas Dupre. CNS Neurol Disord Drug Targets. 2018 Apr 18. doi: 10.2174/1871527317666180419115029. [Epub ahead of print]

The aim of this review is to provide a comprehensive clinical profile and to review the currently available therapies. We overview the physiopathology, neurological features and diagnostic approach of the common recessive ataxias. The emphasis is also made on potential drugs currently or soon-to-be in clinical trials. For instance, promising gene therapies raise the possibility of treating differently Friedreich’s ataxia, Ataxia-telangiectasia, Wilson’s disease and Niemann-Pick disease in the next few years.

Tuesday, May 1, 2018

Cerebellar contribution to locomotor behavior: A neurodevelopmental perspective

Aaron Sathyanesan, Vittorio Gallo, Neurobiology of Learning and Memory, Available online 30 April 2018, ISSN 1074-7427, doi:10.1016/j.nlm.2018.04.016.

The fact that clinicians do not wait till the infant or child reaches the adult stage to intervene therapeutically and measure behavioral outcomes should prompt neuroscientists to rethink how behavior is typically analyzed in pre-clinical animal models of neurodevelopmental disorders.
One of the behavioral hallmarks of early cerebellar injury or childhood onset genetic ataxia is abnormal gait and postural control. Children affected with diseases such as Friedreich’s Ataxia and Ataxia Telangiectasia display gait deficits due to inter- and intra-limb miscoordination, highlighting the importance of cerebellar circuitry to gait control during development.
The biggest advantage of using the Erasmus Ladder is the integration of measuring locomotor performance such as gait dynamics and coordination, as well as an associative, adaptive, conditioned learning paradigm to study cerebellar function

Saturday, April 28, 2018

Clinical management of Friedreich’s Ataxia: a report of two cases

Yannis Dionyssiotis, Athina Kapsokoulou, Anna Danopoulou, Maria Kokolaki & Athina Vadalouka; Spinal Cord Series and Casesvolume 4, Article number: 38 (2018) doi:10.1038/s41394-018-0071-x

We present two cases, a brother (54 years old) and sister (56 years old), with FDRA that are chronically institutionalized for incomplete quadriplegia without spasticity. Gait and postural ataxia, cerebellar dysarthria, oculomotor dysfunction, musculoskeletal deformities, hearing impairment, hypertrophic cardiomyopathy, and diabetes mellitus are also present. Neurological examination reveals extensor plantar responses and diminished to absent tendon reflexes. Both are wheelchair bound, cannot perform daily tasks and need assistance.
Although there is no cure that can alter the natural course of the disease physiotherapy, management of spasticity and neuropathic pain, symptomatic treatment of heart failure and diabetes and nursing care can grant the patients quality of life.

Increased frataxin expression induced in Friedreich ataxia cells by platinum TALE-VP64s or platinum TALE-SunTag

Khadija Cherif, Catherine Gérard, Joël Rousseau, Dominique L. Ouellet, Pierre Chapdelaine, Jacques P. Tremblay, Molecular Therapy - Nucleic Acids, Available online 27 April 2018, ISSN 2162-2531, doi:10.1016/j.omtn.2018.04.009

Frataxin gene (FXN) expression is reduced in Friedreich's ataxia patients due to an increase in the number of GAA trinucleotides in intron 1. The frataxin protein, encoded by that gene, plays an important role in mitochondria’s iron metabolism. Platinum TALE (plTALE) proteins targeting the regulatory region of the FXN gene, fused with a transcriptional activator (TA), such as VP64 or P300, were used to increase the expression of that gene. Many effectors plTALEVP64, plTALEp300 and plTALESunTag targeting 14 sequences of the FXN gene promoter or intron 1 were produced. This permitted to select 3 plTALEVP64s and 2 plTALESunTag that increased FXN gene expression by up to 19 folds in different FRDA primary fibroblasts. Adeno-Associated Viruses were used to deliver the best effectors to the YG8R mouse model to validate their efficiencies in vivo. Our results showed that these selected plTALEVP64s or plTALESunTag induced transcriptional activity of the endogenous FXN gene as well as expression of the frataxin protein in YG8R mouse heart by 10 folds and in skeletal muscles by up to 35 folds. The aconitase activity is positively modulated by the frataxin level in mitochondria and was thus increased in vitro and in vivo by the increased frataxin expression.