Luis Rajman, Karolina Chwalek, David A. Sinclair, Cell Metabolism, Volume 27, Issue 3, 6 March 2018, Pages 529-547, ISSN 1550-4131, doi:10.1016/j.cmet.2018.02.011.
Nicotinamide adenine dinucleotide (NAD), the cell’s hydrogen carrier for redox enzymes, is well known for its role in redox reactions. More recently, it has emerged as a signaling molecule. By modulating NAD+-sensing enzymes, NAD+ controls hundreds of key processes from energy metabolism to cell survival, rising and falling depending on food intake, exercise, and the time of day. NAD+ levels steadily decline with age, resulting in altered metabolism and increased disease susceptibility. Restoration of NAD+ levels in old or diseased animals can promote health and extend lifespan, prompting a search for safe and efficacious NAD-boosting molecules that hold the promise of increasing the body’s resilience, not just to one disease, but to many, thereby extending healthy human lifespan.
Wednesday, March 7, 2018
Friedreich Ataxia: Clinical Report of an Uncommon Point Mutation (R165C)
Rosa María García Tercero*, Javier Gualda Heras, Catalina Diaz Urrea, Pedro Barredo Benitez, Adolfo Heras Pérez, Fátima López González, Blanca serrano Serrano, Elena Elvira Soler and Carmina Díaz Marín; J Neurol Disord 2018, 6:1 DOI:10.4172/2329-6895.1000376
Despite of been inherited as a recessive disease, Friedreich ataxia (FRDA) there is not such clinical homogeneity as in other recessive disorders and due to the atypical presentation of our patient, another sensitives neuropathies were taken into account and a differential diagnosis were made with them (hereditary sensory and autonomic neuropathy, Fabry disease, Familial amyloidotic polyneuropathy, Adrenomyeloneuropathy etc.) but the normality of the probes that have been done and the lack of another symptoms related with these diseases caused that Friedreich ataxia was suspected. With this case we make relevance that not all patients have an early onset, or a severe phenotype and a good neurologic exploration is important to recognize them. Once the diagnosis is made, it is necessary to follow them in consults paying attention to heart problems and giving them genetic counseling.
Despite of been inherited as a recessive disease, Friedreich ataxia (FRDA) there is not such clinical homogeneity as in other recessive disorders and due to the atypical presentation of our patient, another sensitives neuropathies were taken into account and a differential diagnosis were made with them (hereditary sensory and autonomic neuropathy, Fabry disease, Familial amyloidotic polyneuropathy, Adrenomyeloneuropathy etc.) but the normality of the probes that have been done and the lack of another symptoms related with these diseases caused that Friedreich ataxia was suspected. With this case we make relevance that not all patients have an early onset, or a severe phenotype and a good neurologic exploration is important to recognize them. Once the diagnosis is made, it is necessary to follow them in consults paying attention to heart problems and giving them genetic counseling.
Friday, March 2, 2018
Neuroimagem na ataxia de Friedreich = novas abordagens e aplicações clínicas = Neuroimaging in Friedreich's ataxia = new approaches and clinical aplication
Rezende, Thiago Junqueira Ribeiro de; Advisor: França Junior, Marcondes Cavalcante. TESE DIGITAL (2017)(POR)
Abstract: Friedreich¿s ataxia (FRDA) is the most common autosomal-recessive ataxia worldwide; it is characterized by early onset, sensory abnormalities and slowly progressive ataxia. Besides that, most of neuroimaging studies have been focused only in infratentorial structures of adult patients. Furthermore, studies comparing different phenotypes of disease does not exist. Therefore, the objective of this study is to assess, using multimodal magnetic (MRI) resonance imaging, patients with Friedreich ataxia to better comprehend the progression of brain damage, to identify the pattern of damage across disease phenotypes, to identify areas with abnormal iron deposits in the brain and to characterize the structures initially damaged in early disease stages. To accomplish that, we enrolled 25 adult patients with classical FRDA, 13 patients with late-onset FRDA and 12 pediatric patients. The FARS scale was employed to quantify the disease severity. To assess the structural damage in gray and white matter, we acquired T1-weighted, T2-weighted and DTI images of the brain. To evaluate these images, we used the following tools: FreeSurfer, T1 MultiAtlas, SPM, DTI MultiAtlas, SpineSeg and TBSS. After group comparisons, there was widespread microstructural damage in the cerebral white matter, including cerebellar peduncles, corpus callosum and pyramidal tracts of patients with FRDA. We also found gray matter volumetric reduction in the dentate nuclei of the cerebellum, brainstem and motor cortex. We did not find volumetric reduction over time, but there was progressive white matter microstructural damage in the corpus callosum, pyramidal tracts and superior cerebellar peduncles after 1 year of follow-up. Regarding the disease phenotypes, we found that both classical FRDA and LOFA have similar, but not identical neuroimaging signatures. Although subtle, the structural differences might help to explain the phenotypic differences seen in both conditions. The corticospinal tracts are damaged in both conditions, but more severely in the late-onset FRDA group, which may explain why pyramidal signs are more evident in the latter subgroup. We failed to identify iron deposits in brain regions other than the dentate nuclei of patients with FRDA. Finally, we found that the spinal cord and inferior cerebellar peduncles are the structures compromised in pediatric patients with FRDA.
Abstract: Friedreich¿s ataxia (FRDA) is the most common autosomal-recessive ataxia worldwide; it is characterized by early onset, sensory abnormalities and slowly progressive ataxia. Besides that, most of neuroimaging studies have been focused only in infratentorial structures of adult patients. Furthermore, studies comparing different phenotypes of disease does not exist. Therefore, the objective of this study is to assess, using multimodal magnetic (MRI) resonance imaging, patients with Friedreich ataxia to better comprehend the progression of brain damage, to identify the pattern of damage across disease phenotypes, to identify areas with abnormal iron deposits in the brain and to characterize the structures initially damaged in early disease stages. To accomplish that, we enrolled 25 adult patients with classical FRDA, 13 patients with late-onset FRDA and 12 pediatric patients. The FARS scale was employed to quantify the disease severity. To assess the structural damage in gray and white matter, we acquired T1-weighted, T2-weighted and DTI images of the brain. To evaluate these images, we used the following tools: FreeSurfer, T1 MultiAtlas, SPM, DTI MultiAtlas, SpineSeg and TBSS. After group comparisons, there was widespread microstructural damage in the cerebral white matter, including cerebellar peduncles, corpus callosum and pyramidal tracts of patients with FRDA. We also found gray matter volumetric reduction in the dentate nuclei of the cerebellum, brainstem and motor cortex. We did not find volumetric reduction over time, but there was progressive white matter microstructural damage in the corpus callosum, pyramidal tracts and superior cerebellar peduncles after 1 year of follow-up. Regarding the disease phenotypes, we found that both classical FRDA and LOFA have similar, but not identical neuroimaging signatures. Although subtle, the structural differences might help to explain the phenotypic differences seen in both conditions. The corticospinal tracts are damaged in both conditions, but more severely in the late-onset FRDA group, which may explain why pyramidal signs are more evident in the latter subgroup. We failed to identify iron deposits in brain regions other than the dentate nuclei of patients with FRDA. Finally, we found that the spinal cord and inferior cerebellar peduncles are the structures compromised in pediatric patients with FRDA.
Iron Sulfur and Molybdenum Cofactor Enzymes Regulate the Drosophila Life Cycle by Controlling Cell Metabolism
Marelja Z, Leimkühler S and Missirlis F (2018); Front. Physiol. 9:50. doi: 10.3389/fphys.2018.00050
Despite general agreement that frataxin is required for a functional nervous system, disagreement has been expressed on the cause, with different authors favoring oxidative stress (Llorens et al., 2007; Anderson et al., 2008; Kondapalli et al., 2008), iron toxicity (Soriano et al., 2013; Navarro et al., 2015), altered mitochondrial metabolism (Navarro et al., 2010; Tricoire et al., 2014; Calap-Quintana et al., 2015; Soriano et al., 2016), sphingolipid signaling (Chen et al., 2016b), and failure to maintain neuronal membrane potential (Shidara and Hollenbeck, 2010). We do not see any contradiction in the various positive claims made in the above-cited literature, whereas the negative claim that is often repeated—refuting a role for oxidative stress in explaining the phenotypes—normally arises because of failure to rescue the phenotypes with some transgenes as opposed to others.
Despite general agreement that frataxin is required for a functional nervous system, disagreement has been expressed on the cause, with different authors favoring oxidative stress (Llorens et al., 2007; Anderson et al., 2008; Kondapalli et al., 2008), iron toxicity (Soriano et al., 2013; Navarro et al., 2015), altered mitochondrial metabolism (Navarro et al., 2010; Tricoire et al., 2014; Calap-Quintana et al., 2015; Soriano et al., 2016), sphingolipid signaling (Chen et al., 2016b), and failure to maintain neuronal membrane potential (Shidara and Hollenbeck, 2010). We do not see any contradiction in the various positive claims made in the above-cited literature, whereas the negative claim that is often repeated—refuting a role for oxidative stress in explaining the phenotypes—normally arises because of failure to rescue the phenotypes with some transgenes as opposed to others.
Thursday, March 1, 2018
Coenzyme Q10 Supplementation in Aging and Disease
Hernández-Camacho JD, Bernier M, López-Lluch G and Navas P. Front. Physiol. 9:44. doi: 10.3389/fphys.2018.00044
Coenzyme Q (CoQ) is an essential component of the mitochondrial electron transport chain and an antioxidant in plasma membranes and lipoproteins. It is endogenously produced in all cells by a highly regulated pathway that involves a mitochondrial multiprotein complex. Defects in either the structural and/or regulatory components of CoQ complex or in non-CoQ biosynthetic mitochondrial proteins can result in a decrease in CoQ concentration and/or an increase in oxidative stress. Besides CoQ10 deficiency syndrome and aging, there are chronic diseases in which lower levels of CoQ10 are detected in tissues and organs providing the hypothesis that CoQ10 supplementation could alleviate aging symptoms and/or retard the onset of these diseases. Here, we review the current knowledge of CoQ10 biosynthesis and primary CoQ10 deficiency syndrome, and have collected published results from clinical trials based on CoQ10 supplementation. There is evidence that supplementation positively affects mitochondrial deficiency syndrome and the symptoms of aging based mainly on improvements in bioenergetics. Cardiovascular disease and inflammation are alleviated by the antioxidant effect of CoQ10. There is a need for further studies and clinical trials involving a greater number of participants undergoing longer treatments in order to assess the benefits of CoQ10 treatment in metabolic syndrome and diabetes, neurodegenerative disorders, kidney diseases, and human fertility.
Coenzyme Q (CoQ) is an essential component of the mitochondrial electron transport chain and an antioxidant in plasma membranes and lipoproteins. It is endogenously produced in all cells by a highly regulated pathway that involves a mitochondrial multiprotein complex. Defects in either the structural and/or regulatory components of CoQ complex or in non-CoQ biosynthetic mitochondrial proteins can result in a decrease in CoQ concentration and/or an increase in oxidative stress. Besides CoQ10 deficiency syndrome and aging, there are chronic diseases in which lower levels of CoQ10 are detected in tissues and organs providing the hypothesis that CoQ10 supplementation could alleviate aging symptoms and/or retard the onset of these diseases. Here, we review the current knowledge of CoQ10 biosynthesis and primary CoQ10 deficiency syndrome, and have collected published results from clinical trials based on CoQ10 supplementation. There is evidence that supplementation positively affects mitochondrial deficiency syndrome and the symptoms of aging based mainly on improvements in bioenergetics. Cardiovascular disease and inflammation are alleviated by the antioxidant effect of CoQ10. There is a need for further studies and clinical trials involving a greater number of participants undergoing longer treatments in order to assess the benefits of CoQ10 treatment in metabolic syndrome and diabetes, neurodegenerative disorders, kidney diseases, and human fertility.
Tuesday, February 27, 2018
Commentary: Novelty Seeking and Reward Dependence-Related Large-Scale Brain Networks Functional Connectivity Variation During Salience Expectancy
Cristiano Crescentini. Front. Psychol. doi: 10.3389/fpsyg.2018.00242 (General Commentary ARTICLE Provisionally accepted, The full-text will be published soon)
In recent years several neuropsychological and psychiatry studies employed the psychobiological model of temperament and character to investigate the relationship between personality and neuropsychological function in patients with Parkinson’s disease, Friedreich Ataxia, attention-deficit/hyperactivity disorder, eating disorders, and antisocial behavior.
These studies indicated that alterations in personality and cognition are not independent from each other, in that poor development of specific personality traits appears to be associated with deficits in neuropsychological performance, in particular in advanced cognition such as executive functions.
In recent years several neuropsychological and psychiatry studies employed the psychobiological model of temperament and character to investigate the relationship between personality and neuropsychological function in patients with Parkinson’s disease, Friedreich Ataxia, attention-deficit/hyperactivity disorder, eating disorders, and antisocial behavior.
These studies indicated that alterations in personality and cognition are not independent from each other, in that poor development of specific personality traits appears to be associated with deficits in neuropsychological performance, in particular in advanced cognition such as executive functions.
Monday, February 26, 2018
GAA•TTC repeat expansion in human cells is mediated by mismatch repair complex MutLγ and depends upon the endonuclease domain in MLH3 isoform one
Anasheh Halabi Kayla T B Fuselier Ed Grabczyk. Nucleic Acids Research, gky143, doi:10.1093/nar/gky143
DNA repeat expansion underlies dozens of progressive neurodegenerative disorders. While the mechanisms driving repeat expansion are not fully understood, increasing evidence suggests a central role for DNA mismatch repair. The mismatch repair recognition complex MutSβ (MSH2-MSH3) that binds mismatched bases and/or insertion/deletion loops has previously been implicated in GAA•TTC, CAG•CTG and CGG•CCG repeat expansion, suggesting a shared mechanism. MutSβ has been studied in a number of models, but the contribution of subsequent steps mediated by the MutL endonuclease in this pathway is less clear. Here we show that MutLγ (MLH1-MLH3) is the MutL complex responsible for GAA•TTC repeat expansion. Lentiviral expression of shRNA targeting MutL nuclease components MLH1, PMS2, and MLH3 revealed that reduced expression of MLH1 or MLH3 reduced the repeat expansion rate in a human Friedreich ataxia cell model, while targeting PMS2 did not. Using splice-switching oligonucleotides we show that MLH3 isoform 1 is active in GAA•TTC repeat expansion while the nuclease-deficient MLH3 isoform 2 is not. MLH3 isoform switching slowed repeat expansion in both model cells and FRDA patient fibroblasts. Our work indicates a specific and active role for MutLγ in the expansion process and reveals plausible targets for disease-modifying therapies.
DNA repeat expansion underlies dozens of progressive neurodegenerative disorders. While the mechanisms driving repeat expansion are not fully understood, increasing evidence suggests a central role for DNA mismatch repair. The mismatch repair recognition complex MutSβ (MSH2-MSH3) that binds mismatched bases and/or insertion/deletion loops has previously been implicated in GAA•TTC, CAG•CTG and CGG•CCG repeat expansion, suggesting a shared mechanism. MutSβ has been studied in a number of models, but the contribution of subsequent steps mediated by the MutL endonuclease in this pathway is less clear. Here we show that MutLγ (MLH1-MLH3) is the MutL complex responsible for GAA•TTC repeat expansion. Lentiviral expression of shRNA targeting MutL nuclease components MLH1, PMS2, and MLH3 revealed that reduced expression of MLH1 or MLH3 reduced the repeat expansion rate in a human Friedreich ataxia cell model, while targeting PMS2 did not. Using splice-switching oligonucleotides we show that MLH3 isoform 1 is active in GAA•TTC repeat expansion while the nuclease-deficient MLH3 isoform 2 is not. MLH3 isoform switching slowed repeat expansion in both model cells and FRDA patient fibroblasts. Our work indicates a specific and active role for MutLγ in the expansion process and reveals plausible targets for disease-modifying therapies.
Friday, February 23, 2018
BMN 290 for Friedreich's Ataxia
News provided by BioMarin Pharmaceutical Inc.; SAN RAFAEL, Calif., Feb. 22, 2018 /PRNewswire/
In the fourth quarter of 2017, BioMarin announced that it had selected as its next drug development candidate, BMN 290, a selective chromatin modulation therapy intended for treatment of Friedreich's ataxia. Friedreich's ataxia is a rare autosomal recessive disorder that results in disabling neurologic and cardiac progressive decline. Prior to the compound being acquired by BioMarin from Repligen Corporation (Repligen), it demonstrated increases in frataxin in Friedreich's ataxia patients. In preclinical models, BMN 290 increases frataxin expression in brain tissues more than two-fold. The Company selected BMN 290 for its favorable penetration into the central nervous system and cardiac target tissues, and its preservation of the selectivity of the original Repligen compound. Currently, there are no approved disease modifying therapies for Friedreich's ataxia. The Company expects to submit the IND application for BMN 290 in the second half of 2018.
In the fourth quarter of 2017, BioMarin announced that it had selected as its next drug development candidate, BMN 290, a selective chromatin modulation therapy intended for treatment of Friedreich's ataxia. Friedreich's ataxia is a rare autosomal recessive disorder that results in disabling neurologic and cardiac progressive decline. Prior to the compound being acquired by BioMarin from Repligen Corporation (Repligen), it demonstrated increases in frataxin in Friedreich's ataxia patients. In preclinical models, BMN 290 increases frataxin expression in brain tissues more than two-fold. The Company selected BMN 290 for its favorable penetration into the central nervous system and cardiac target tissues, and its preservation of the selectivity of the original Repligen compound. Currently, there are no approved disease modifying therapies for Friedreich's ataxia. The Company expects to submit the IND application for BMN 290 in the second half of 2018.
Thursday, February 22, 2018
Mapping the Structural Determinants Required for AAVrh.10 Transport across the Blood-Brain Barrier
Blake H. Albright, Claire M. Storey, Giridhar Murlidharan, Ruth M. Castellanos Rivera, Garrett E. Berry, Victoria J. Madigan, Aravind Asokan; Molecular Therapy, Volume 26, Issue 2, p510–523, 7 February 2018 DOI: 10.1016/j.ymthe.2017.10.017
Effective gene delivery to the CNS by intravenously administered adeno-associated virus (AAV) vectors requires crossing the blood-brain barrier (BBB). To achieve therapeutic CNS transgene expression, high systemic vector doses are often required, which poses challenges such as scale-up costs and dose-dependent hepatotoxicity. To improve the specificity and efficiency of CNS gene transfer, a better understanding of the structural features that enable AAV transit across the BBB is needed. We generated a combinatorial domain swap library using AAV1, a serotype that does not traverse the vasculature, and AAVrh.10, which crosses the BBB in mice. We then screened individual variants by phylogenetic and structural analyses and subsequently conducted systemic characterization in mice. Using this approach, we identified key clusters of residues on the AAVrh.10 capsid that enabled transport across the brain vasculature and widespread neuronal transduction in mice. Through rational design, we mapped a minimal footprint from AAVrh.10, which, when grafted onto AAV1, confers the aforementioned CNS phenotype while diminishing vascular and hepatic transduction through an unknown mechanism. Functional mapping of this capsid surface footprint provides a roadmap for engineering synthetic AAV capsids for efficient CNS gene transfer with an improved safety profile.
Effective gene delivery to the CNS by intravenously administered adeno-associated virus (AAV) vectors requires crossing the blood-brain barrier (BBB). To achieve therapeutic CNS transgene expression, high systemic vector doses are often required, which poses challenges such as scale-up costs and dose-dependent hepatotoxicity. To improve the specificity and efficiency of CNS gene transfer, a better understanding of the structural features that enable AAV transit across the BBB is needed. We generated a combinatorial domain swap library using AAV1, a serotype that does not traverse the vasculature, and AAVrh.10, which crosses the BBB in mice. We then screened individual variants by phylogenetic and structural analyses and subsequently conducted systemic characterization in mice. Using this approach, we identified key clusters of residues on the AAVrh.10 capsid that enabled transport across the brain vasculature and widespread neuronal transduction in mice. Through rational design, we mapped a minimal footprint from AAVrh.10, which, when grafted onto AAV1, confers the aforementioned CNS phenotype while diminishing vascular and hepatic transduction through an unknown mechanism. Functional mapping of this capsid surface footprint provides a roadmap for engineering synthetic AAV capsids for efficient CNS gene transfer with an improved safety profile.
Hepcidin, an emerging and important player in brain iron homeostasis
Driton Vela. Journal of Translational Medicine 201816:25 doi:10.1186/s12967-018-1399-5
Iron dysregulation has been observed consistently in different organs in Friedreich ataxia (FA). This disease affects CNS by causing neurodegenerative damages in dentate nuclei of the cerebellum, dorsal root ganglia, but also in cerebrum, thalamus and other structures. FA is caused by a defective frataxin, which main functions include involvement in iron-sulfur cluster formation and in iron delivery to ferrochelatase. Although some observations did find iron accumulation in dentate nuclei in FA patients, other studies have revealed a pattern of iron redistribution, rather than iron accumulation in FA. Studies suggest that iron dysregulation in FA is not needed for neurodegeneration to occur, while animal models reveal tissue-specific damages due to frataxin deficiency. These differences are related with levels of frataxin expression, where most of the damage is observed in tissues with higher expression of frataxin, such as the heart and dorsal root ganglia. In the heart, inflammatory infiltrate produces hepcidin and has been proposed as one of the pathogenic mechanisms of heart damage in FA. Frataxin deficiency in animal models can cause a strong inflammatory reaction in Schwann cells, which are known to enwrap neurons of dorsal root ganglia. These neurons are frequently affected in FA and are characterized with iron dysregulation and inappropriate myelination. But, hepcidin expression in these cells has not been studied in models of FA, therefore it is not known what role, if any, does hepcidin have in the pathophysiology of neurodegeneration in FA.
Iron dysregulation has been observed consistently in different organs in Friedreich ataxia (FA). This disease affects CNS by causing neurodegenerative damages in dentate nuclei of the cerebellum, dorsal root ganglia, but also in cerebrum, thalamus and other structures. FA is caused by a defective frataxin, which main functions include involvement in iron-sulfur cluster formation and in iron delivery to ferrochelatase. Although some observations did find iron accumulation in dentate nuclei in FA patients, other studies have revealed a pattern of iron redistribution, rather than iron accumulation in FA. Studies suggest that iron dysregulation in FA is not needed for neurodegeneration to occur, while animal models reveal tissue-specific damages due to frataxin deficiency. These differences are related with levels of frataxin expression, where most of the damage is observed in tissues with higher expression of frataxin, such as the heart and dorsal root ganglia. In the heart, inflammatory infiltrate produces hepcidin and has been proposed as one of the pathogenic mechanisms of heart damage in FA. Frataxin deficiency in animal models can cause a strong inflammatory reaction in Schwann cells, which are known to enwrap neurons of dorsal root ganglia. These neurons are frequently affected in FA and are characterized with iron dysregulation and inappropriate myelination. But, hepcidin expression in these cells has not been studied in models of FA, therefore it is not known what role, if any, does hepcidin have in the pathophysiology of neurodegeneration in FA.
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