Amandine Palandri, Elodie Martin, Maria Russi, Michael Rera, Hervé Tricoire, Véronique Monnier, Disease Models & Mechanisms 2018 : dmm.033811 doi: 10.1242/dmm.033811 Published 13 June 2018
In conclusion, this pharmacological screen led to the identification of 11 drugs that significantly reduced heart dilatation of frataxin-depleted hearts. This study may lead in the future to therapeutic applications and improves our knowledge of the mechanisms involved in cardiac dysfunction associated with FA disease. In particular, it suggests that decreased contractility and dilatation of frataxin depleted hearts are, at least in part, a consequence of defective sarcomeric assembly due to microtubule destabilisation. More generally, our data highlight the power of Drosophila models of cardiac diseases for pharmacological approaches. We show here that it is feasible to perform pharmacological screens in vivo on a relatively large scale, under physiological conditions and using relevant functional parameters as readouts. This type of approach could therefore be extended in the future to a wide panel of cardiac diseases.
Friday, June 15, 2018
Saturday, June 9, 2018
Role of ROS and Nutritional Antioxidants in Human Diseases
Zewen Liu, Zhangpin Ren, Jun Zhang, Chia-Chen Chuang, Eswar Kandaswamy, Tingyang Zhou, and Li Zuo; Front Physiol. 2018; 9: 477. doi:10.3389/fphys.2018.00477
The combination of vitamin E and coenzyme Q10 improves energy generation in some cases of Friedreich ataxia by attenuating OS and restoring mitochondrial function. Numerous studies have been performed to investigate the therapeutic effects of natural antioxidants on neurodegenerative disorders; however, mixed results have been yielded.
The combination of vitamin E and coenzyme Q10 improves energy generation in some cases of Friedreich ataxia by attenuating OS and restoring mitochondrial function. Numerous studies have been performed to investigate the therapeutic effects of natural antioxidants on neurodegenerative disorders; however, mixed results have been yielded.
RNA Editing and Retrotransposons in Neurology
Heinz Krestel and Jochen C. Meier; Front Mol Neurosci. 2018; 11: 163. doi:10.3389/fnmol.2018.00163
Friedreich ataxia is the best known and most commonly inherited form of spinocerebellar ataxia. It can be caused by mutations or, in 98% of cases, by GAA trinucleotide-repeat expansions located at the center of an AluSq element in intron 1 of the frataxin (FXN) gene. Friedreich ataxia is the only known disease caused by abnormal expansion of a GAA trinucleotide-repeat sequence. It was suggested that GAA repeats arose by mutation or A-to-G conversion from poly(A) tracts of Alu elements. Many longer GAA repeats in the human genome can be found in the 3′ poly(A) tracts of Alu elements, but it was suggested that A-to-G conversion that led to poly-GAA repeats in Friedreich ataxia arose in the central linker region of Alu elements. Beyond GAA repeats, Alu elements were in general described to be a source for microsatellites. Expansion of trinucleotide repeats was proposed to have arisen in Friedreich ataxia rather by in-tandem duplication up to a certain repeat length. From a certain repeat length onwards, genetic instability was proposed to contribute to additional repeat expansion, which is known in Neurology as anticipation. GAA repeat expansions affect pre-mRNA processing by inducing the accumulation of upstream splicing intermediates. No interaction of RNA editing with these genetic rearrangements in Friedreich ataxia has been reported.
Friedreich ataxia is the best known and most commonly inherited form of spinocerebellar ataxia. It can be caused by mutations or, in 98% of cases, by GAA trinucleotide-repeat expansions located at the center of an AluSq element in intron 1 of the frataxin (FXN) gene. Friedreich ataxia is the only known disease caused by abnormal expansion of a GAA trinucleotide-repeat sequence. It was suggested that GAA repeats arose by mutation or A-to-G conversion from poly(A) tracts of Alu elements. Many longer GAA repeats in the human genome can be found in the 3′ poly(A) tracts of Alu elements, but it was suggested that A-to-G conversion that led to poly-GAA repeats in Friedreich ataxia arose in the central linker region of Alu elements. Beyond GAA repeats, Alu elements were in general described to be a source for microsatellites. Expansion of trinucleotide repeats was proposed to have arisen in Friedreich ataxia rather by in-tandem duplication up to a certain repeat length. From a certain repeat length onwards, genetic instability was proposed to contribute to additional repeat expansion, which is known in Neurology as anticipation. GAA repeat expansions affect pre-mRNA processing by inducing the accumulation of upstream splicing intermediates. No interaction of RNA editing with these genetic rearrangements in Friedreich ataxia has been reported.
Epigenetic Regulation in Neurodegenerative Diseases
Amit Berson, Raffaella Nativio, Shelley L. Berger, Nancy M. Bonini, Trends in Neurosciences, Available online 7 June 2018, ISSN 0166-2236, doi:10.1016/j.tins.2018.05.005.
Mechanisms of epigenetic regulation, including DNA methylation, chromatin remodeling, and histone post-translational modifications, are involved in multiple aspects of neuronal function and development. Recent discoveries have shed light on critical functions of chromatin in the aging brain, with an emerging realization that the maintenance of a healthy brain relies heavily on epigenetic mechanisms. Here, we present recent advances, with a focus on histone modifications and the implications for several neurodegenerative diseases including Alzheimer’s disease (AD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). We highlight common and unique epigenetic mechanisms among these situations and point to emerging therapeutic approaches.
Mechanisms of epigenetic regulation, including DNA methylation, chromatin remodeling, and histone post-translational modifications, are involved in multiple aspects of neuronal function and development. Recent discoveries have shed light on critical functions of chromatin in the aging brain, with an emerging realization that the maintenance of a healthy brain relies heavily on epigenetic mechanisms. Here, we present recent advances, with a focus on histone modifications and the implications for several neurodegenerative diseases including Alzheimer’s disease (AD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). We highlight common and unique epigenetic mechanisms among these situations and point to emerging therapeutic approaches.
Wednesday, June 6, 2018
Adding a temporal dimension to the study of Friedreich's ataxia: the effect of frataxin overexpression in a human cell model
Tommaso Vannocci, Roberto Notario Manzano, Ombretta Beccalli, Barbara Bettegazzi, Fabio Grohovaz, Gianfelice Cinque, Antonio de Riso, Luca Quaroni, Franca Codazzi, Annalisa Pastore
Disease Models & Mechanisms 2018 : dmm.032706 doi: 10.1242/dmm.032706 Published 24 May 2018
We prove that overexpression of the frataxin gene affects the cellular metabolism. It also lead to a significant increase of oxidative stress and labile iron pool levels. These cellular alterations are similar to those observed when the gene is partially silenced, as it occurs in Friedreich's ataxia's patients. Our data suggest that the levels of frataxin must be tightly regulated and fine-tuned, any imbalance leading to oxidative stress and toxicity.
Viral approaches (AAV), take advantage of a human exogenous FXN gene under the control of strong promoters that induce overexpression of the therapeutic genes. Although the mouse models showed great improvements, the lack of a tight control on the levels of expression could generate the effects detailed in this work with unknown long-term consequences for patients treated this way. Recent studies have taken advantage of the novel CRISPR gene editing approach to produce the desired gene correction as an alternative, gene correction of the endogenous FXN gene by reduction of the GAA expansion seems to be preferable. This strategy has the advantage that frataxin levels would be restored to physiological levels. It is however essential for these studies to determine the effects of different levels of frataxin.
Disease Models & Mechanisms 2018 : dmm.032706 doi: 10.1242/dmm.032706 Published 24 May 2018
We prove that overexpression of the frataxin gene affects the cellular metabolism. It also lead to a significant increase of oxidative stress and labile iron pool levels. These cellular alterations are similar to those observed when the gene is partially silenced, as it occurs in Friedreich's ataxia's patients. Our data suggest that the levels of frataxin must be tightly regulated and fine-tuned, any imbalance leading to oxidative stress and toxicity.
Viral approaches (AAV), take advantage of a human exogenous FXN gene under the control of strong promoters that induce overexpression of the therapeutic genes. Although the mouse models showed great improvements, the lack of a tight control on the levels of expression could generate the effects detailed in this work with unknown long-term consequences for patients treated this way. Recent studies have taken advantage of the novel CRISPR gene editing approach to produce the desired gene correction as an alternative, gene correction of the endogenous FXN gene by reduction of the GAA expansion seems to be preferable. This strategy has the advantage that frataxin levels would be restored to physiological levels. It is however essential for these studies to determine the effects of different levels of frataxin.
Rehabilitation robots for the treatment of sensorimotor deficits: a neurophysiological perspective
Roger Gassert and Volker Dietz; Journal of NeuroEngineering and Rehabilitation 2018 15:46 doi:10.1186/s12984-018-0383-x
Future rehabilitation approaches will not only profit from the inclusion of robots, but also from an advanced understanding of neurophysiological mechanisms underlying normal and impaired sensorimotor functions, enabled by the use of robots as scientific tools. Resulting insights will benefit the development of advanced rehabilitation robots, and further promote collaboration between engineers, therapists and clinical neurophysiologists.
Future rehabilitation approaches will not only profit from the inclusion of robots, but also from an advanced understanding of neurophysiological mechanisms underlying normal and impaired sensorimotor functions, enabled by the use of robots as scientific tools. Resulting insights will benefit the development of advanced rehabilitation robots, and further promote collaboration between engineers, therapists and clinical neurophysiologists.
Oligonucleotides Hold Promise as a Therapy for Friedreich's Ataxia: Friedreich's ataxia currently is incurable, but synthetic antisense oligonucleotides have demonstrated promising results in increasing frataxin gene expression and restoring it to normal levels
AJMG. Volume176, Issue6 June 2018 Pages 1282-1282 doi:10.1002/ajmg.a.38850
Another important point that was demonstrated in this and previous papers is that oligonucleotides increase the expression of FXN. According to Dr. Corey, “That corrects a fundamental defect in the disease specifically at the gene level, so it is a plausible compound for moving forward.”
However, right now the compounds are in the earliest stages, and more evidence is needed that the treatment is safe and effective. “We need to find animal models to begin testing it, and a company needs to be encouraged to develop it,” Dr. Corey says.
Another important point that was demonstrated in this and previous papers is that oligonucleotides increase the expression of FXN. According to Dr. Corey, “That corrects a fundamental defect in the disease specifically at the gene level, so it is a plausible compound for moving forward.”
However, right now the compounds are in the earliest stages, and more evidence is needed that the treatment is safe and effective. “We need to find animal models to begin testing it, and a company needs to be encouraged to develop it,” Dr. Corey says.
Sunday, June 3, 2018
Modelling the dorsal root ganglia using human pluripotent stem cells: A platform to study peripheral neuropathies
Serena Viventi, Mirella Dottori, The International Journal of Biochemistry & Cell Biology, Volume 100, July 2018, Pages 61-68, ISSN 1357-2725, doi:10.1016/j.biocel.2018.05.005.
Sensory neurons of the dorsal root ganglia (DRG) are the primary responders to stimuli inducing feelings of touch, pain, temperature, vibration, pressure and muscle tension. They consist of multiple subpopulations based on their morphology, molecular and functional properties. Our understanding of DRG sensory neurons has been predominantly driven by rodent studies and using transformed cell lines, whereas less is known about human sensory DRG neurons simply because of limited availability of human tissue. Although these previous studies have been fundamental for our understanding of the sensory system, it is imperative to profile human DRG subpopulations as it is becoming evident that human sensory neurons do not share the identical molecular and functional properties found in other species. Furthermore, there are wide range of diseases and disorders that directly/indirectly cause sensory neuronal degeneration or dysfunctionality. Having an in vitro source of human DRG sensory neurons is paramount for studying their development, unique neuronal properties and for accelerating regenerative therapies to treat sensory neuropathies. Here we review the major studies describing generation of DRG sensory neurons from human pluripotent stem cells and fibroblasts and the gaps that need to be addressed for using in vitro-generated human DRG neurons to model human DRG tissue.
There are vast ranges of diseases and conditions, usually progressive, which can affect DRG sensory neurons. The underlying causes of DRG degeneration may be either directly intrinsic to DRG neurons or indirectly associated with other pathologies. Some inherited genetic diseases inducing DRG degeneration include Friedreich’s Ataxia and Charcot Marie Tooth Disease
Sensory neurons of the dorsal root ganglia (DRG) are the primary responders to stimuli inducing feelings of touch, pain, temperature, vibration, pressure and muscle tension. They consist of multiple subpopulations based on their morphology, molecular and functional properties. Our understanding of DRG sensory neurons has been predominantly driven by rodent studies and using transformed cell lines, whereas less is known about human sensory DRG neurons simply because of limited availability of human tissue. Although these previous studies have been fundamental for our understanding of the sensory system, it is imperative to profile human DRG subpopulations as it is becoming evident that human sensory neurons do not share the identical molecular and functional properties found in other species. Furthermore, there are wide range of diseases and disorders that directly/indirectly cause sensory neuronal degeneration or dysfunctionality. Having an in vitro source of human DRG sensory neurons is paramount for studying their development, unique neuronal properties and for accelerating regenerative therapies to treat sensory neuropathies. Here we review the major studies describing generation of DRG sensory neurons from human pluripotent stem cells and fibroblasts and the gaps that need to be addressed for using in vitro-generated human DRG neurons to model human DRG tissue.
There are vast ranges of diseases and conditions, usually progressive, which can affect DRG sensory neurons. The underlying causes of DRG degeneration may be either directly intrinsic to DRG neurons or indirectly associated with other pathologies. Some inherited genetic diseases inducing DRG degeneration include Friedreich’s Ataxia and Charcot Marie Tooth Disease
Tuesday, May 29, 2018
TLR-activated repression of Fe-S cluster biogenesis drives a metabolic shift and alters histone and tubulin acetylation
Wing-Hang Tong, Nunziata Maio, De-Liang Zhang, Erika M. Palmieri, Hayden Ollivierre, Manik C. Ghosh, Daniel W. McVicar and Tracey A. Rouault; Blood Advances 2018 2:1146-1156; doi: doi:10.1182/bloodadvances.2018015669
hese results reveal new regulatory pathways and novel roles of the Fe-S cluster biogenesis machinery in modifying the epigenome and acetylome and provide new insights into the etiology of Fe-S cluster biogenesis disorders.
Interestingly, we showed that silencing of FXN and ISCU resulted in increased MEC17 levels and increased α-tubulin acetylation.
Extensive chromatin immunoprecipitation data collected at the FRDA locus, which contains an expanded trinucleotide repeat (GAA)n in the first intron of FXN, had shown that the levels of the heterochromatin mark H3K9me3 were enriched, whereas the levels of acetylated H3 and H4 were reduced. Our finding that decreased Fe-S cluster biogenesis resulted in decreased overall histone acetylation and increased H3K9me3 levels poses an interesting possibility of a negative feedback mechanism that potentiates a progressive loss of FXN expression in the postmitotic cells that are most severely affected in FRDA. Furthermore, our results showed that silencing of Fe-S cluster biogenesis factors reduced the levels of ELP3, a subunit of the Elongator complex that has roles in growth cone motility and axonal outgrowth. In addition, our studies revealed that silencing of FXN or ISCU induced the α-tubulin acetyltransferase MEC17, resulting in hyperacetylation of α-tubulin. Reversible acetylation of tubulin confers mechanical protection to microtubules51 and controls their interaction with cellular components52 and is critical for neuronal development and function, growth factor or apoptotic signaling, and cell cycle progression. Acetylation of K40 of α-tubulin is mainly controlled by the cytosolic acetyltransferase MEC17 and the cytosolic deacetylases HDAC6 and SIRT2. Notably, a mouse model of FRDA cardiomyopathy with ablation of FXN had increased mitochondrial protein acetylation that was attributed to a decrease in the mitochondrial NAD+/NADH ratio, which can lower the activity of the mitochondrial deacetylase SIRT3. Thus, our findings suggest that the roles of PDHc, ELP3, and MEC17 in the etiology of FRDA, GLRX5-related sideroblastic anemias, and other Fe-S cluster biogenesis disorders warrant further study.
hese results reveal new regulatory pathways and novel roles of the Fe-S cluster biogenesis machinery in modifying the epigenome and acetylome and provide new insights into the etiology of Fe-S cluster biogenesis disorders.
Interestingly, we showed that silencing of FXN and ISCU resulted in increased MEC17 levels and increased α-tubulin acetylation.
Extensive chromatin immunoprecipitation data collected at the FRDA locus, which contains an expanded trinucleotide repeat (GAA)n in the first intron of FXN, had shown that the levels of the heterochromatin mark H3K9me3 were enriched, whereas the levels of acetylated H3 and H4 were reduced. Our finding that decreased Fe-S cluster biogenesis resulted in decreased overall histone acetylation and increased H3K9me3 levels poses an interesting possibility of a negative feedback mechanism that potentiates a progressive loss of FXN expression in the postmitotic cells that are most severely affected in FRDA. Furthermore, our results showed that silencing of Fe-S cluster biogenesis factors reduced the levels of ELP3, a subunit of the Elongator complex that has roles in growth cone motility and axonal outgrowth. In addition, our studies revealed that silencing of FXN or ISCU induced the α-tubulin acetyltransferase MEC17, resulting in hyperacetylation of α-tubulin. Reversible acetylation of tubulin confers mechanical protection to microtubules51 and controls their interaction with cellular components52 and is critical for neuronal development and function, growth factor or apoptotic signaling, and cell cycle progression. Acetylation of K40 of α-tubulin is mainly controlled by the cytosolic acetyltransferase MEC17 and the cytosolic deacetylases HDAC6 and SIRT2. Notably, a mouse model of FRDA cardiomyopathy with ablation of FXN had increased mitochondrial protein acetylation that was attributed to a decrease in the mitochondrial NAD+/NADH ratio, which can lower the activity of the mitochondrial deacetylase SIRT3. Thus, our findings suggest that the roles of PDHc, ELP3, and MEC17 in the etiology of FRDA, GLRX5-related sideroblastic anemias, and other Fe-S cluster biogenesis disorders warrant further study.
Saturday, May 26, 2018
Peripheral blood gene expression reveals an inflammatory transcriptomic signature in Friedreich’s ataxia patients
Daniel Nachun, Fuying Gao, Charles Isaacs, Cassandra Strawser, Zhongan Yang, Deepika Dokuru, Victoria Van Berlo, Renee Sears, Jennifer Farmer, Susan Perlman, David R Lynch, Giovanni Coppola; Human Molecular Genetics, ddy198, doi:10.1093/hmg/ddy198
We identified a transcriptional signature strongly enriched for an inflammatory innate immune response. Future studies should seek to further characterize the role of peripheral inflammation in FRDA pathology and determine its relevance to overall disease progression.
We identified a transcriptional signature strongly enriched for an inflammatory innate immune response. Future studies should seek to further characterize the role of peripheral inflammation in FRDA pathology and determine its relevance to overall disease progression.
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