Inside HDACs with more selective HDAC inhibitors

Joëlle Roche, Philippe Bertrand, European Journal of Medicinal Chemistry, Available online 25 May 2016, ISSN 0223-5234, doi: 10.1016/j.ejmech.2016.05.047.

Inhibitors of histone deacetylases (HDACs) are nowadays part of the therapeutic arsenal mainly against cancers, with four compounds approved by the Food and Drug Administration.During the last five years, several groups have made continuous efforts to improve this class of compounds, designing more selective compounds or compounds with multiple capacities. After a survey of the HDACs biology and structures, this review summarizes the results of the chemists working in this field, and highlights when possible the behaviour of the molecules inside their targets.

Associated disease: Friedreich's ataxia. Partners: Interacts with HDAC7 and HDAC9; DAXX, HDAC10 and DACH1; BCOR, MJD2A/JHDM3A, NRIP1, PRDM6 and SRY, BTBD14B, GLIS2, NR2C1; CBFA2T3 and NKAP; APEX1, MAPK14, ZMYND15, SMRT/NCOR2 and BCL6, INSM1, XBP1 isoform 1, CCAR2, MEF2D, BEND3. Forms a heterologous complex at least with YY1, It may participate in the regulation of transcription through its binding with the zinc-finger transcription factor YY1. Found in a complex with NCOR1 and NCOR2. Component of the N-Cor repressor complex. Component of the Notch corepressor complex. Functions: This protein can also down-regulate p53 function and thus modulate cell growth and apoptosis. This gene is regarded as a potential tumour suppressor gene.

Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich’s ataxia

R Abeti, M H Parkinson, I P Hargreaves, P R Angelova, C Sandi, M A Pook, P Giunti and A Y Abramov. Cell Death and Disease (2016) 7, e2237; doi:10.1038/cddis.2016.111 Published online 26 May 2016

Open

Although the role of frataxin is largely known, being fundamental for the iron biogenesis in the cell, the relation between frataxin and mitochondrial bioenergetics is not completely clear.

We assessed the type of mitochondrial dysfunction that was present in the cerebellum, concluding that Complex I activity is impaired, but Complex II compensates by overworking. Therefore, if we consider the ETC, we can define the mitochondrial dysfunction as a mildly defective bioenergetic phenotype. However, this mild dysfunction drives the formation of free radicals that cannot be attenuated by the endogenous antioxidant systems, which are downregulated. Thus, the level of lipid peroxidation increases dramatically, damaging the cells and causing premature cell death. Therefore, lipid peroxidation could be a potential target for future therapeutic approaches in FRDA.

Mutations in the substrate binding glycine-rich loop of the mitochondrial processing peptidase-α protein (PMPCA) cause a severe mitochondrial disease

Mugdha Joshi, Irina Anselm, Jiahai Shi, Tejus A. Bale, Meghan Towne, Klaus Schmitz-Abe, Laura Crowley, Felix C. Giani, Shideh Kazerounian, Kyriacos Markianos, Hart G. Lidov, Rebecca Folkerth, Vijay G. Sankaran, and Pankaj B. Agrawal. Cold Spring Harb Mol Case Stud. 2016 May; 2(3): a000786. doi:10.1101/mcs.a000786


This study describes a severe mitochondrial disease due to PMPCA mutations in a large family, which we show is associated with altered levels of mature frataxin. Whereas a recent study described cerebellar ataxia as a presentation of PMPCA mutations, the phenotype in our family is more severe and typical of a mitochondrial disease. The observed phenotype may be related to impaired PMPCA function due to a reduction in its level and the resultant abnormal processing of frataxin and other mitochondrial proteins.

Open Access
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://​creativecommons.​org/​licenses/​by/​4.​0/​)

JOT101, a product for treatment of Friedreich’s ataxia.

Jupiter, Florida (PRWEB) May 25, 2016, by Christer Rosén, Jupiter Orphan Therapeutics.

Jupiter Orphan Therapeutics, Inc. (JOT) today announced that world renowned scientist David Sinclair, Ph.D. joined JOT as Co-Chairman of its Scientific Advisory Board (SAB).

Dr. Sinclair was contacted by his fellow scientists, Prof Martin Delatycki from Murdoch Childrens Research Institute, Australia (MCRI), who informed him of the resveratrol JOTROL product that was developed by JOT. JOT has a global license from MCRI regarding developing JOT101, a product for treatment of Friedreich’s ataxia.

Dr. Sinclair stated “I am excited about being able to work with JOT to bring drugs to patients who are waiting for a solution to their rare disease. JOTROL opens up the possibility that resveratrol will finally realize its potential to revolutionize human health.”

Purkinje cell injury, structural plasticity and fusion in patients with Friedreich’s ataxia

Kevin C. Kemp, Amelia J. Cook, Juliana Redondo, Kathreena M. Kurian, Neil J. Scolding and Alastair Wilkins. Acta Neuropathologica CommunicationsNeuroscience of Disease20164:53. DOI: 10.1186/s40478-016-0326-3

For the first time in a genetic condition, we have also shown a disease-related increase in the frequency of Purkinje cell fusion and heterokaryon formation in Friedreich's ataxia cases; with evidence that underlying levels of cerebellar inflammation influence heterokaryon formation. Our results together further demonstrate the Purkinje cell’s unique plasticity and regenerative potential.

Understanding whether Purkinje cell axon remodelling and/or fusion represent mechanisms by which cerebellar functions can be maintained in genetic cerebellar disease has important therapeutic consequences. With the potential to protect and rescue neuronal cells and restore homeostatic balance during neurodegeneration, understanding the circumstances in which they occur may lead to techniques to manipulate these mechanisms therapeutically.

Open Access.
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://​creativecommons.​org/​licenses/​by/​4.​0/​)

Longitudinal strain bull's eye plot patterns in patients with cardiomyopathy and concentric left ventricular hypertrophy.

Dan Liu, Kai Hu, Peter Nordbeck, Georg Ertl, Stefan Störk and Frank Weidemann. European Journal of Medical Research 201621:21 DOI: 10.1186/s40001-016-0216-y

Friedreich’s ataxia: Besides the neurologic manifestation, cardiac involvement and endocrine involvement are also frequent. A concentric LVH with an end-diastolic wall thickness of less than 15 mm is the usual echocardiographic feature. Around 40 % of FA patients show concentric remodeling, 35 % show concentric hypertrophy and only 5 % display an eccentric hypertrophy. Global systolic function and diastolic function remain normal in most FA patients, and only end-stage FA patients develop reduced EF with global hypokinesia and slightly dilated LV chamber.

Electrocardiographic abnormalities (ST-T changes) are often the earliest sign of FA cardiomyopathy. At this early stage, echocardiography results are usually normal and the longitudinal strain bull’s eye plot is similar pattern as healthy subjects (Fig. 7a). In FA patients with concentric LVH and normal EF, the bull’s eye plot pattern presents with a mildly reduced average global strain (Fig. 7b). Myocardial fibrosis develops gradually, leading to LV wall thinning and LV dilatation during the disease progression, while EF remains preserved for a long time until the end-stage of the disease. Of note, the LV wall thinning appears to be diffuse in FA cardiomyopathy, which is different from the typical findings in Fabry cardiomyopathy. The bull’s eye plot shows significantly reduced average global longitudinal strain when LVEF is reduced (Fig. 7c).

CMRI with LE imaging provides evidence of fibrosis in the advanced stage of this disease, suggesting that fibrosis might be associated with subsequent myocardial dysfunction.

Open Access
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://​creativecommons.​org/​licenses/​by/​4.​0/​)

Role of XPD in cellular functions: to TFIIH and beyond

Bennett Van Houten, Jochen Kuper, Caroline Kisker, DNA Repair, Available online 16 May 2016, ISSN 1568-7864, doi: 10.1016/j.dnarep.2016.05.019.

One interesting implication of this work is in cells deficient in iron-sulfur cluster biogenesis, such as those from patients with Friedreich ataxia (FA), since several key DNA processing proteins, such as XPD, DDX11, FANCJ and RTEL1 contain FeS centers, these patients displayed an RNA expression pattern similar to cells undergoing a DNA damage respons. FA patients might be expected to have higher levels of DNA damage. It has recently been observed that these patients have altered telomeres because RTEL1 activity is lower.

The epidemiology of neuromuscular disorders: Age at onset and gender in the Netherlands

Johanna C.W. Deenen, Pieter A. van Doorn, Catharina G. Faber, Anneke J. van der Kooi, Jan B.M. Kuks, Nicolette C. Notermans, Leo H. Visser, Corinne G.C. Horlings, Jan J.G.M. Verschuuren, André L.M. Verbeek, Baziel G.M. van Engelen, Neuromuscular Disorders, Available online 21 April 2016, ISSN 0960-8966, doi:10.1016/j.nmd.2016.04.011

Based on approximately eight years of data collection with the nationwide Computer Registry of All Myopathies and Polyneuropathies (CRAMP) in the Netherlands, recent epidemiologic information for thirty neuromuscular disorders is presented. Friedreich's Ataxia is included. These data may be helpful in the diagnostic process in clinical practice and trial readiness.

Horizon Pharma plc to Acquire Worldwide Rights to Interferon Gamma-1b From Boehringer Ingelheim International GmbH

18 May 2016 | Marketwired.

"Obtaining worldwide rights for interferon gamma-1b solidifies our continued investment in the medicine, and pending the outcome of clinical studies investigating it in Friedreich's ataxia and advanced solid tumors, such as kidney and bladder cancer, strengthens our ability to expand its potential global use"

Under the terms of a separate agreement with an undisclosed third party, Horizon Pharma also licensed the U.S., European and Canadian intellectual property rights for interferon gamma-1b for the treatment of Friedreich's ataxia. Interferon gamma-1b is currently not indicated or approved for the treatment of Friedreich's ataxia.

Movimientos anormales y embarazo / Abnormal movements and pregnancy

Eduardo Palacios, Ángela Viviana Navas, Repertorio de Medicina y Cirugía, Available online 30 April 2016, ISSN 0121-7372, doi:10.1016/j.reper.2016.04.001.

OPEN ACCESS

Los estudios en este grupo de pacientes son escasos y antiguos dada la baja prevalencia.
Las mujeres con FA tienen una supervivencia más larga que los hombres, lo cual permite más años potenciales de maternidad durante las etapas avanzadas de la enfermedad. En la mayor serie, las complicaciones maternas más significativas fueron cardiacas y endocrinas; sin embargo, la capacidad para llevar a término el embarazo no fue afectada ni se presentaron malformaciones congénitas.