Depression disorder in patients with cerebellar damage: Awareness of the mood state

ilvia Clausi, Michela Lupo, Giusy Olivito, Libera Siciliano, Maria Pia Contento, Fabio Aloise, Luigi Pizzamiglio, Marco Molinari, Maria Leggio. Journal of Affective Disorders, Volume 245, 2019, Pages 386-393, doi:10.1016/j.jad.2018.11.029.

Cerebellar dysfunction might slow the data integration necessary for mood state awareness, resulting in difficulty of depressed CB patients in explicitly recognizing their mood “in the here and now”.
In conclusion, cerebellar involvement in the conscious component of emotional behaviour, related to awareness of one's affective state and interpretation of one's mood, may contribute to a loss of the‘online’ self-perception of negative mood that characterizes depressive disorders in the presence of cerebellar pathology. These data may help explain why depression in cerebellar patients is often underdiagnosed.

Paradoxical disruption of Nrf2 signaling despite mitochondrial iron driven oxidative stress in Friedreich’s ataxia cardiomyopathy

Michael Huang, Amy Anzovino, Shannon Chiang, Bronwyn Brown, Clare Hawkins, Des Richardson. Free Radical Biology and Medicine, Volume 128, Supplement 1, 2018, Page S131, doi.org/10.1016/j.freeradbiomed.2018.10.346

Cardiomyopathy is the leading cause of mortality for the most prevalent inherited ataxia, Friedreich’s ataxia (FA). Deficient expression of the mitochondrial protein frataxin that is crucial for mitochondrial iron metabolism is the cause of FA, which exhibits marked mitochondrial Fe accumulation. Our studies using a conditional cardiac frataxin knockout (KO) mouse that mirrors FA cardiomyopathy have shown frataxin deletion leads to pronounced trafficking of cardiac iron from the cytosol to the mitochondrion, leading to a cytosolic iron-deficiency and mitochondrial iron accumulation in the form of non-protein-bound, biomineral iron aggregates. The ensuing oxidative stress is likely a key contributor to FA pathology. The transcription factor, nuclear factor E2-related factor 2 (Nrf2), is the master regulator of cellular antioxidant response. In the frataxin KO mouse, our studies demonstrated increased protein and GSH oxidation in the KO relative to wild-type (WT) littermates. Despite this, we found paradoxical decreases in total and nuclear Nrf2 protein and an increase in its inhibitor, Keap1, which mediates Nrf2 degradation in the cytosol. Moreover, a mechanism involving activation of the nuclear Nrf2 export/degradation machinery via Gsk3β-signaling was found in the KO heart. This is evident by: (i) increased Gsk3β activation; (ii) increased Fyn-mediated nuclear Nrf2 export; and (iii) increased expression of β-TrCP that is involved in Nrf2 degradation. Furthermore, a corresponding decrease in Nrf2-DNA-binding activity and a general decrease in Nrf2-target mRNA was observed in KO heart. Collectively, despite marked mitochondrial iron accumulation in FA cardiomyopathy, Nrf2 activity was disrupt via two mechanisms: increased Keap1 that decreases cytosolic Nrf2, and the activation of Gsk3β-signaling that decreases nuclear Nrf2.

Del deseo a la realidad: la edición genética (aún) no está preparada para tratar a pacientes

SINC, la ciencia es noticia (17 noviembre 2018). Lluís Montoliu, es investigador científico del Centro Nacional de Biotecnología (CNB-CSIC) y Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER-ISCIII), además de miembro del Comité de Ética del CSIC.

Las terapias génicas basadas en CRISPR para curar enfermedades todavía tardarán en llegar. Quizás no sea este el titular que quisiéramos leer, pero es el mensaje que hay que repetir para no generar falsas expectativas sobre esta potente herramienta de corta-pega genético.

Hoy en día se están desarrollando múltiples variantes de la técnica CRISPR, a cual más innovadora e imaginativa. Algunas de ellas son extremadamente prometedoras, como los editores de bases, una evolución de las herramientas CRISPR capaz de cambiar nucleótidos concretos del genoma sin necesidad de cortarlo. Pero todas ellas conllevan todavía riesgos inaceptables, tanto en seguridad como en eficacia, para saltar al hospital.

Son métodos sofisticados que nos permiten abordar experimentos en el laboratorio como nunca antes habíamos podido hacerlo, pero que todavía no pueden trasladarse a la clínica. Necesitan de mucho más trabajo, mucha más investigación en el laboratorio.

Mitochondrial calcium signalling and neurodegenerative diseases

Elena Britti, Fabien Delaspre, Jordi Tamarit, Joaquim Ros; Neuronal Signaling Dec 2018, 2 (4) NS20180061; DOI: 10.1042/NS20180061

Mitochondrial calcium homoeostasis clearly contributes to cellular fitness and survival. Maintenance of accurate calcium levels is highly regulated by mitochondrial proteins that are connected, either directly or via other proteins, to ER calcium stores. As described in this review, prior to cell death, mitochondrial calcium deregulation could be the consequence of increased influx (MCU complex), or decreased efflux (Na+/Ca2+ exchanger) or altered capacity for calcium buffering caused by mitochondrial damage, such as MPTP opening. Calcium deregulation would then lead to several neurodegenerative processes that resulted in cell death. Thus, identifying specific targets to maintain calcium balance and mitochondrial function appears to be of paramount importance in preventing, alleviating or even curing neurodegenerative diseases.
Although the initial steps of the process through which decreased levels of frataxin leads to neurodegeneration are still unknown, the above-reported findings clearly point to an important role of calcium deregulation in the pathophysiology of FA. Therapeutic strategies that impact on the proteins responsible for calcium overload and its consequences could be of great value for developing a cure for the disease.

FAST-1 antisense RNA epigenetically alters FXN expression

Hajar Mikaeili, Madhavi Sandi, Aurélien Bayot, Sahar Al-Mahdawi & Mark A. Pook; Scientific Reports, volume 8, Article number: 17217 (2018). doi:10.1038/s41598-018-35639-2

Our results show that knocking down FAST-1 in FRDA fibroblast cells increases FXN gene expression (Fig. 10). Therefore, it can be concluded that, since FAST-1 is associated with epigenetic repression of the FXN gene, inhibition of FAST-1 may be an approach to increase the FXN transcripts and stimulate subsequent protein expression. Indeed, our results demonstrate that knocking down FAST-1 in FRDA results in a significant increase in aconitase enzyme activity, a good indicator of frataxin function within cells. Our data suggest that since FAST-1 is associated with FXN gene silencing, inhibition of FAST-1 may be an approach for FRDA therapy. Considering the nature of NATs and the fact that many currently available drugs would not affect the activity of non-coding RNA molecules, developing new methods to disrupt the function of NATs seems necessary.

NMR as a Tool to Investigate the Processes of Mitochondrial and Cytosolic Iron-Sulfur Cluster Biosynthesis

Cai, K.; Markley, J.L.; Molecules 2018, 23, 2213. doi:10.3390/molecules23092213

Defects in protein components of the mitochondrial ISC machinery are associated with numerous diseases, including Friedreich ataxia (defects in frataxin), myopathy (defects in ISCU or FDX2), and multiple mitochondrial dysfunction syndromes (defects in NFU1, BOLA3, ISCA2, and IBA57). Extensive investigations over the past two decades have identified many new components and established key steps in the ISC machinery. A growing number of diseases associated with ISC defects are being discovered through clinical, genetic, and biochemical studies.

Characterization of a new N-terminally acetylated extra-mitochondrial isoform of frataxin in human erythrocytes

Lili Guo, Qingqing Wang, Liwei Weng, Lauren A. Hauser, Cassandra J. Strawser, Clementina Mesaros, David R. Lynch & Ian A. Blair; Scientific Reports volume 8, Article number:17043 (2018) DOI:10.1038/s41598-018-35346-y

The mitochondrial form of frataxin has long been thought to be present in erythrocytes even though paradoxically, erythrocytes lack mitochondria. We have discovered that erythrocyte frataxin is in fact a novel isoform of frataxin (isoform E) with 135-amino acids and an N-terminally acetylated methionine residue. There is three times as much isoform E in erythrocytes (20.9 ± 6.4 ng/mL) from the whole blood of healthy volunteers (n = 10) when compared with the mature mitochondrial frataxin present in other blood cells (7.1 ± 1.0 ng/mL). Isoform E lacks a mitochondrial targeting sequence and so is distributed to both cytosol and the nucleus when expressed in cultured cells. When extra-mitochondrial frataxin isoform E is expressed in HEK 293 cells, it is converted to a shorter isoform identical to the mature frataxin found in mitochondria, which raises the possibility that it is involved in disease etiology. The ability to specifically quantify extra-mitochondrial and mitochondrial isoforms of frataxin in whole blood will make it possible to readily follow the natural history of diseases such as Friedreich’s ataxia and monitor the efficacy of therapeutic interventions.

Emerging and Dynamic Biomedical Uses of Ferritin

Brian Chiou and James R. Connor; Pharmaceuticals 2018, 11(4), 124; doi:10.3390/ph11040124

Review

One interesting new development has been proposed in Friedreich’s Ataxia where the authors discuss the hypothesis that the mitochondrial protein frataxin may oligomerize like ferritin and perform functions redundant with mitochondrial ferritin, acting as another iron storage molecule. Loss of frataxin and this iron storage property may result in Friedreich’s Ataxia and subsequent neurodegeneration.

Evidence supporting regulatory-decision making on orphan medicinal products authorisation in Europe: methodological uncertainties

Caridad Pontes, Juan Manuel Fontanet, Roser Vives, Aranzazu Sancho, Mònica Gómez-Valent, José Ríos, Rosa Morros, Jorge Martinalbo, Martin Posch, Armin Koch, Kit Roes, Katrien Oude Rengerink, Josep Torrent-Farnell and Ferran Torres; Orphanet Journal of Rare Diseases 2018 13:206 doi:10.1186/s13023-018-0926-z

The regulatory evidence supporting OMP authorization showed substantial uncertainties, including weak protection against errors, substantial use of designs unsuited for conclusions on causality, use of intermediate variables, lack of a priorism and insufficient safety data to quantify risks of relevant magnitude. Grouping medical conditions based on clinical features and their methodological requirements may facilitate specific methodological and regulatory recommendations for the study of OMP to strengthen the evidence base.

Plasma Markers of Neurodegeneration Are Raised in Friedreich’s Ataxia

Zeitlberger Anna M., Thomas-Black Gilbert, Garcia-Moreno Hector, Foiani Martha, Heslegrave Amanda J., Zetterberg Henrik, Giunti Paola; Frontiers in Cellular Neuroscience 2018, 12 366, DOI=10.3389/fncel.2018.00366

This study provides the first assessment of plasma markers of neurodegeneration in FRDA, illustrating that NfL, GFAP, and UCHL1 are significantly raised in FRDA compared to aged-matched control. These observations may serve as the basis of further exploration of these brain-derived proteins as promising biomarkers in FRDA. In addition, we show for the first time in vivo an increase of GFAP reflecting astrocyte activation. This is confirmatory of in vitro studies suggesting a role of astrocytes in FRDA pathology. Finally, UCHL1 increase may reflect non-specific neuronal damage or alterations in the UPP. Future studies are needed to confirm our findings and determine whether, when applied to more heterogeneous cohorts, they serve as useful markers of disease severity.