Gessica Vasco , Simone Gazzellini, Maurizio Petrarca, Maria Luisa Lispi, Alessandra Pisano, Marco Zazza, Gessica Della Bella, Enrico Castelli, Enrico Bertini, PLoS ONE 11(9): e0162463. doi:10.1371/journal.pone.0162463
Open access
Wednesday, September 7, 2016
Tuesday, September 6, 2016
Comparative Mitochondrial-Based Protective Effects of Resveratrol and Nicotinamide in Huntington’s Disease Models
Luana Naia, Tatiana R. Rosenstock, Ana M. Oliveira, Sofia I. Oliveira-Sousa, Gladys L. Caldeira, Catarina Carmo, Mário N. Laço, Michael R. Hayden, Catarina R. Oliveira, A. Cristina Rego; Mol Neurobiol (2016). doi:10.1007/s12035-016-0048-3
In this study, we tested the influence of resveratrol (RESV, a SIRT1 activator) versus nicotinamide (NAM, a SIRT1 inhibitor) in counteracting mitochondrial dysfunction in HD models. Further studies revealed decreased PGC-1α and TFAM protein levels, linked to mitochondrial DNA loss in HD lymphoblasts. Remarkably, RESV completely restored these parameters, while NAM increased NAD+ levels, providing a positive add on mitochondrial function in in vitro HD models. In general, RESV decreased while NAM increased H3 acetylation at lysine 9. In agreement with in vitro data, continuous RESV treatment for 28 days significantly improved motor coordination and learning and enhanced expression of mitochondrial-encoded electron transport chain genes in YAC128 mice. In contrast, high concentrations of NAM blocked mitochondrial-related transcription, worsening motor phenotype. Overall, data indicate that activation of deacetylase activity by RESV improved gene transcription associated to mitochondrial function in HD, which may partially control HD-related motor disturbances.
In this study, we tested the influence of resveratrol (RESV, a SIRT1 activator) versus nicotinamide (NAM, a SIRT1 inhibitor) in counteracting mitochondrial dysfunction in HD models. Further studies revealed decreased PGC-1α and TFAM protein levels, linked to mitochondrial DNA loss in HD lymphoblasts. Remarkably, RESV completely restored these parameters, while NAM increased NAD+ levels, providing a positive add on mitochondrial function in in vitro HD models. In general, RESV decreased while NAM increased H3 acetylation at lysine 9. In agreement with in vitro data, continuous RESV treatment for 28 days significantly improved motor coordination and learning and enhanced expression of mitochondrial-encoded electron transport chain genes in YAC128 mice. In contrast, high concentrations of NAM blocked mitochondrial-related transcription, worsening motor phenotype. Overall, data indicate that activation of deacetylase activity by RESV improved gene transcription associated to mitochondrial function in HD, which may partially control HD-related motor disturbances.
Friedreich ataxia induced pluripotent stem cell-derived neurons show a cellular phenotype that is corrected by a benzamide HDAC inhibitor
Franca Codazzi, Amelié Hu, Myriam Rai, Floramarida Salerno Scarzella, Elisabeth Mangiameli, Ilaria Pelizzoni, Fabio Grohovaz and Massimo Pandolfo3; Hum. Mol. Genet. (2016) doi: 10.1093/hmg/ddw308 First published online: September 4, 2016
Findings suggest that correction of frataxin deficiency may not only stop disease progression, but also lead to clinical improvement by rescuing still surviving, but dysfunctional neurons.
Findings suggest that correction of frataxin deficiency may not only stop disease progression, but also lead to clinical improvement by rescuing still surviving, but dysfunctional neurons.
Monday, September 5, 2016
R loops and links to human disease
Patricia Richard, James L. Manley, Journal of Molecular Biology, Available online 4 September 2016, ISSN 0022-2836, doi:10.1016/j.jmb.2016.08.031.
More than 40 genetic disorders are caused by gene-specific repeat expansions. These include Huntington’s disease (HD) (CAG repeats in huntingtin (HTT)), myotonic dystrophy type 1 (MD1) (CTG repeats in dystrophia myotonica protein kinase (DMPK)), spinocerebellar ataxia type 1 (SCA1) (CAG repeats in ataxin1 (ATXN1)), fragile X mental retardation or fragile X syndrome (FXS) (CGG repeats in fragile X mental retardation 1 (FMR1)) and Friedreich ataxia (FDRA) (GAA repeats in frataxin (FXN)).
More than 40 genetic disorders are caused by gene-specific repeat expansions. These include Huntington’s disease (HD) (CAG repeats in huntingtin (HTT)), myotonic dystrophy type 1 (MD1) (CTG repeats in dystrophia myotonica protein kinase (DMPK)), spinocerebellar ataxia type 1 (SCA1) (CAG repeats in ataxin1 (ATXN1)), fragile X mental retardation or fragile X syndrome (FXS) (CGG repeats in fragile X mental retardation 1 (FMR1)) and Friedreich ataxia (FDRA) (GAA repeats in frataxin (FXN)).
Friday, September 2, 2016
Biomarkers and progress of antioxidant therapy for rare mitochondrial disorders
Lucia Chico, Daniele Orsucci, Annalisa Lo Gerfo, Letizia Marconi, Michelangelo Mancuso & Gabriele Siciliano. Expert Opinion on Orphan Drugs Volume 4, Issue 6, 2016, DOI:10.1080/21678707.2016.1178570
Promising clinical trials have been recently described including the use of different compounds and molecules that can reduce oxidative stress levels and simultaneously act as electron carriers to modulate mitochondrial electron flow.
Several compounds and therapies have been demonstrated to possess mitochondrial restoring and antioxidant properties such as vitamins and cofactors like Coenzyme Q10 (CoQ10) folic acid, vitamin B12, riboflavin, L-carnitine, and creatine, electron acceptors like vitamin C, free radical scavengers like idebenone, EPI-743, vitamin E, alpha lipoic acid, and curcumin, inhibitors of toxic metabolites (dicholoroacetate). Therapeutic potentials of these compounds have been suggested to restoring mitochondrial functions, transport and synaptic plasticity, and showed some neuroprotective role not only in rare mitochondrial disease, but also in other neurodegenerative disorders.
More evidence supports also the use of a combination of “mitococktails”, this referring to as the combination of several and different vitamins, with antioxidant supplements tailored for individual patients to increase mitochondrial respiration and scavenge free radicals to reduce ROS produced in mitochondria diseases.
Promising clinical trials have been recently described including the use of different compounds and molecules that can reduce oxidative stress levels and simultaneously act as electron carriers to modulate mitochondrial electron flow.
Several compounds and therapies have been demonstrated to possess mitochondrial restoring and antioxidant properties such as vitamins and cofactors like Coenzyme Q10 (CoQ10) folic acid, vitamin B12, riboflavin, L-carnitine, and creatine, electron acceptors like vitamin C, free radical scavengers like idebenone, EPI-743, vitamin E, alpha lipoic acid, and curcumin, inhibitors of toxic metabolites (dicholoroacetate). Therapeutic potentials of these compounds have been suggested to restoring mitochondrial functions, transport and synaptic plasticity, and showed some neuroprotective role not only in rare mitochondrial disease, but also in other neurodegenerative disorders.
More evidence supports also the use of a combination of “mitococktails”, this referring to as the combination of several and different vitamins, with antioxidant supplements tailored for individual patients to increase mitochondrial respiration and scavenge free radicals to reduce ROS produced in mitochondria diseases.
Wednesday, August 31, 2016
Pharmacological treatments for Friedreich ataxia
Kearney M, Orrell RW, Fahey M, Brassington R, Pandolfo M. Pharmacological treatments for Friedreich ataxia. Cochrane Database of Systematic Reviews 2016, Issue 8. Art. No.: CD007791. DOI: 10.1002/14651858.CD007791.pub4.
Tuesday, August 30, 2016
Optimization of pyrimidinol antioxidants as mitochondrial protective agents: ATP production and metabolic stability
Arnaud Chevalier, Mohammad Parvez Alam, Omar M. Khdour, Margaret Schmierer, Pablo M. Arce, Cameron D. Cripe, Sidney M. Hecht,Bioorganic & Medicinal Chemistry, Available online 23 August 2016, ISSN 0968-0896, doi:10.1016/j.bmc.2016.08.039.
The compounds were evaluated for their ability to suppress ROS and lipid peroxidation, and for their effects on mitochondrial membrane potential, and their ability to protect cultured FRDA lymphocytes from oxidative stress induced by glutathione depletion. The compounds were also evaluated for their ability to increase ATP levels in FRDA lymphocytes.
The compounds were evaluated for their ability to suppress ROS and lipid peroxidation, and for their effects on mitochondrial membrane potential, and their ability to protect cultured FRDA lymphocytes from oxidative stress induced by glutathione depletion. The compounds were also evaluated for their ability to increase ATP levels in FRDA lymphocytes.
Monday, August 29, 2016
Neurobehavioral deficits in the KIKO mouse model of Friedreich's ataxia
Marissa Z. McMackin, Chelsea K. Henderson, Gino A. Cortopassi, Behavioural Brain Research SreeTestContent1 SreeTestContent1, Available online 26 August 2016, ISSN 0166-4328, doi:/10.1016/j.bbr.2016.08.053.
The KIKO mouse is an animal model of FA with frataxin deficiency first described in 2002, but neurobehavioral deficits have never been described in this model. The identification of robust neurobehavioral deficits in KIKO mice could support the testing of drugs for FA.
The KIKO mouse is an animal model of FA with frataxin deficiency first described in 2002, but neurobehavioral deficits have never been described in this model. The identification of robust neurobehavioral deficits in KIKO mice could support the testing of drugs for FA.
Sunday, August 28, 2016
Blood–brain barrier shuttle peptides: an emerging paradigm for brain delivery
Benjamí Oller-Salvia, Macarena Sánchez-Navarro, Ernest Giralt and Meritxell Teixidó, (Review Article) Chem. Soc. Rev., 2016, 45, 4690-4707 DOI: 10.1039/C6CS00076B
Open Access Article
Although the BBB remains a formidable obstacle, since the Trojan horse concept was coined in the 1980s, the field of drug delivery to the brain has made remarkable progress. In the last few years, a plethora of new BBB shuttle peptides have emerged and hold great promise to overcome the limitations of the first generation of shuttles dominated by large proteins. Peptides are more affordable, easier to characterize and to link to nanocarriers or proteins. Moreover, they have lower immunogenicity and often have a reduced effect on the activity of the cargo than their larger counterparts. Furthermore, many peptide shuttles do not compete with endogenous substrates in contrast to endogenous proteins, nor stay bound to the receptor unlike some antibodies. BBB shuttle peptides have so far provided promising results in terms of brain delivery in preclinical settings. In addition, a relevant increase in the therapeutic effect has been proven in a wide variety of animal disease models, with a focus on brain tumours but also including neurodegenerative and lysosomal diseases as well as epilepsy among others.
Despite the considerable achievements described, new shuttles with higher transport capacity and selectivity are required. Approaches like phage display and natural sources of peptides that reach the CNS offer an excellent opportunity to explore the multitude of poorly characterized or still unknown routes into the brain. These strategies should be complemented with additional efforts in the characterization of the transport mechanisms and in global proteomic approaches to identify new receptors. Also, further comparative studies between shuttles and a more accurate quantification of the free drug in the brain parenchyma would enable a more efficient identification and optimization of BBB shuttles. The next generation of BBB shuttle peptides should aim for an enhanced metabolic stability, a higher transendothelial transport and an improved selectivity for the brain – even for particular regions of this organ – possibly through yet uncharacterized transctytotic pathways.
Acknowledgements: IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain). We appreciate financial support from MINECO-FEDER (Bio2013-40716-R and CTQ2013-49462-EXP), MINECO (PCIN-2015-051 Cure2DIPG), RecerCaixa-2014-Gate2Brain, Generalitat de Catalunya (XRB and 2014-SGR-521), FARA and GENEFA. B.O.-S. and M.S.-N. are grateful for “La Caixa”/IRB Barcelona and Juan de la Cierva fellowships, respectively.
Open Access Article
Although the BBB remains a formidable obstacle, since the Trojan horse concept was coined in the 1980s, the field of drug delivery to the brain has made remarkable progress. In the last few years, a plethora of new BBB shuttle peptides have emerged and hold great promise to overcome the limitations of the first generation of shuttles dominated by large proteins. Peptides are more affordable, easier to characterize and to link to nanocarriers or proteins. Moreover, they have lower immunogenicity and often have a reduced effect on the activity of the cargo than their larger counterparts. Furthermore, many peptide shuttles do not compete with endogenous substrates in contrast to endogenous proteins, nor stay bound to the receptor unlike some antibodies. BBB shuttle peptides have so far provided promising results in terms of brain delivery in preclinical settings. In addition, a relevant increase in the therapeutic effect has been proven in a wide variety of animal disease models, with a focus on brain tumours but also including neurodegenerative and lysosomal diseases as well as epilepsy among others.
Despite the considerable achievements described, new shuttles with higher transport capacity and selectivity are required. Approaches like phage display and natural sources of peptides that reach the CNS offer an excellent opportunity to explore the multitude of poorly characterized or still unknown routes into the brain. These strategies should be complemented with additional efforts in the characterization of the transport mechanisms and in global proteomic approaches to identify new receptors. Also, further comparative studies between shuttles and a more accurate quantification of the free drug in the brain parenchyma would enable a more efficient identification and optimization of BBB shuttles. The next generation of BBB shuttle peptides should aim for an enhanced metabolic stability, a higher transendothelial transport and an improved selectivity for the brain – even for particular regions of this organ – possibly through yet uncharacterized transctytotic pathways.
Acknowledgements: IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain). We appreciate financial support from MINECO-FEDER (Bio2013-40716-R and CTQ2013-49462-EXP), MINECO (PCIN-2015-051 Cure2DIPG), RecerCaixa-2014-Gate2Brain, Generalitat de Catalunya (XRB and 2014-SGR-521), FARA and GENEFA. B.O.-S. and M.S.-N. are grateful for “La Caixa”/IRB Barcelona and Juan de la Cierva fellowships, respectively.
CONTINUUM: Lifelong Learning in Neurology
Ashizawa, Tetsuo MD, FAAN; Xia, Guangbin MD, PhD; August 2016 - Volume 22 - Issue 4, Movement Disorders - p 1208–1226 doi: 10.1212/CON.0000000000000362
Purpose of Review: This article introduces the background and common etiologies of ataxia and provides a general approach to assessing and managing the patient with ataxia.
Purpose of Review: This article introduces the background and common etiologies of ataxia and provides a general approach to assessing and managing the patient with ataxia.
Subscribe to:
Posts (Atom)
