Tauroursodeoxycholic bile acid arrests axonal degeneration by inhibiting the unfolded protein response in X-linked adrenoleukodystrophy

Altres ajuts: We are indebted to the NIH NeuroBioBank for supplying the case material used for the human studies. This study was supported by grants from the European Leukodystrophy Association [ELA2012-033C1], the Center for Biomedical Research on Rare Diseases (CIBERER) to N.L. and M.R. Locomotor experiments were performed by the SEFALer unit F5 led by A.P. which belongs to the CIBERER structure.The online version of this article (doi:10.1007/s00401-016-1655-9) contains supplementary material, which is available to authorized users

Inactivation of the peroxisomal ABCD2 transporter in the mouse leads to late-onset ataxia involving mitochondria, Golgi and endoplasmic reticulum damage

ATP-binding cassette (ABC) transporters facilitate unidirectional translocation of chemically diverse substances, ranging from peptides to lipids, across cell or organelle membranes. In peroxisomes, a subfamily of four ABC transporters (ABCD1 to ABCD4) has been related to fatty acid transport, because patients with mutations in ABCD1 (ALD gene) suffer from X-linked adrenoleukodystrophy (X-ALD), a disease characterized by an accumulation of very-long-chain fatty acids (VLCFAs). Inactivation in the mouse of the abcd1 gene leads to a late-onset neurodegenerative condition, comparable to the late-onset form of X-ALD [Pujol, A., Hindelang, C., Callizot, N., Bartsch, U., Schachner, M. and Mandel, J.L. (2002) Late onset neurological phenotype of the X-ALD gene inactivation in mice: a mouse model for adrenomyeloneuropathy. Hum. Mol. Genet., 11, 499-505.]. In the present work, we have generated and characterized a mouse deficient for abcd2, the closest paralog to abcd1. The main pathological feature in abcd2−/− mice is a late-onset cerebellar and sensory ataxia, with loss of cerebellar Purkinje cells and dorsal root ganglia cell degeneration, correlating with accumulation of VLCFAs in the latter cellular population. Axonal degeneration was present in dorsal and ventral columns in spinal cord. We have identified mitochondrial, Golgi and endoplasmic reticulum damage as the underlying pathological mechanism, thus providing evidence of a disturbed organelle cross-talk, which may be at the origin of the pathological cascad

Caracterización de los partos pretérminos en el Hospital "Vladimir Ilich Lenin" de Holguín / Characterization of preterm births at "Vladimir Ilich Lenin" Hospital in Holguin

Introducción: La prematuridad constituye un problema médico debido a su elevada mortalidad y la complejidad del cuidado perinatal al que se somete el producto de la concepción.Objetivo: Caracterizar los partos pretérminos en el Hospital Docente Universitario "Vladimir Ilich Lenin" de Holguín.Métodos: Se realizó un estudio descriptivo, observacional en el servicio de Obstetricia en Hospital Docente Universitario "Vladimir Ilich Lenin" de Holguín, durante el periodo de enero de 2017 y diciembre de 2022. El universo estuvo conformado por 1 658 nacimientos durante el periodo de estudio, con una muestra de 411 seleccionados, a partir de un muestreo no probabilístico intencionado.Resultados: El 52,4 % del total de partos durante el año 2022 fueron pretérminos, y de ellos el 13,9 % fueron espontáneos. Entre las causas más comunes se encuentran las restricciones del crecimiento intrauterino, para un 44,3 %. La mayor incidencia de inminencia de prematuridad se encontró entre las 34- 36,6 semanas, para un 54,9 %. Predominan los partos pretérminos espontáneos entre las 34-36,6 semanas de gestación, con un 86,9 %.Conclusiones: El Servicio de Obstetricia de la provincia Holguín cuenta con una estrategia encaminada a la prevención del parto pretérmino. La disminución de la incidencia de los partos pretérminos espontáneos, sumado a que la inminencia de prematuridad se presente durante las 34 a 36,6 semanas y a que un mayor porcentaje de gestaciones alcanza dichas semanas. Estos son datos que reflejan la efectividad de esta estrategia y sustentan su posible aplicación en otras instituciones

Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations

Transcription disequilibria are characteristic of many neurodegenerative diseases. The activity-evoked transcription of immediate early genes (IEGs), important for neuronal plasticity, memory and behavior, is altered in CNS diseases and governed by epigenetic modulation. KDM1A, a histone 3 lysine 4 demethylase that forms part of transcription regulation complexes, has been implicated in the control of IEG transcription. Here we report the development of vafidemstat (ORY-2001), a brain penetrant inhibitor of KDM1A and MAOB. ORY-2001 efficiently inhibits brain KDM1A at doses suitable for long term treatment, and corrects memory deficit as assessed in the novel object recognition testing in the Senescence Accelerated Mouse Prone 8 (SAMP8) model for accelerated aging and Alzheimer's disease. Comparison with a selective KDM1A or MAOB inhibitor reveals that KDM1A inhibition is key for efficacy. ORY-2001 further corrects behavior alterations including aggression and social interaction deficits in SAMP8 mice and social avoidance in the rat rearing isolation model. ORY-2001 increases the responsiveness of IEGs, induces genes required for cognitive function and reduces a neuroinflammatory signature in SAMP8 mice. Multiple genes modulated by ORY-2001 are differentially expressed in Late Onset Alzheimer's Disease. Most strikingly, the amplifier of inflammation S100A9 is highly expressed in LOAD and in the hippocampus of SAMP8 mice, and down-regulated by ORY-2001. ORY-2001 is currently in multiple Phase IIa studies

Autophagy induction halts axonal degeneration in a mouse model of x-adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD) is a rare neurometabolic disease characterized by the accumulation of very long chain fatty acids (VLCFAs) due to a loss of function of the peroxisomal transporter ABCD1. Here, using in vivo and in vitro models, we demonstrate that autophagic flux was impaired due to elevated mammalian target of rapamycin (mTOR) signaling, which contributed to X-ALD pathogenesis. We also show that excess VLCFAs downregulated autophagy in human fibroblasts. Furthermore, mTOR inhibition by a rapamycin derivative (temsirolimus) restored autophagic flux and inhibited the axonal degenerative process as well as the associated locomotor impairment in the Abcd1 (-) /Abcd2 (-/-) mouse model. This process was mediated through the restoration of proteasome function and redox as well as metabolic homeostasis. These findings provide the first evidence that links impaired autophagy to X-ALD, which may yield a therapy based on autophagy activators for adrenomyeloneuropathy patients

Tauroursodeoxycholic bile acid arrests axonal degeneration by inhibiting the unfolded protein response in X-linked adrenoleukodystrophy

The activation of the highly conserved unfolded protein response (UPR) is prominent in the pathogenesis of the most prevalent neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), which are classically characterized by an accumulation of aggregated or misfolded proteins. This activation is orchestrated by three endoplasmic reticulum (ER) stress sensors: PERK, ATF6 and IRE1. These sensors transduce signals that induce the expression of the UPR gene programme. Here, we first identified an early activator of the UPR and investigated the role of a chronically activated UPR in the pathogenesis of X-linked adrenoleukodystrophy (X-ALD), a neurometabolic disorder that is caused by ABCD1 malfunction; ABCD1 transports very long-chain fatty acids (VLCFA) into peroxisomes. The disease manifests as inflammatory demyelination in the brain or and/or degeneration of corticospinal tracts, thereby resulting in spastic paraplegia, with the accumulation of intracellular VLCFA instead of protein aggregates. Using X-ALD mouse model (Abcd1 - and Abcd1 - /Abcd2 -/- mice) and X-ALD patient's fibroblasts and brain samples, we discovered an early engagement of the UPR. The response was characterized by the activation of the PERK and ATF6 pathways, but not the IRE1 pathway, showing a difference from the models of AD, PD or ALS. Inhibition of PERK leads to the disruption of homeostasis and increased apoptosis during ER stress induced in X-ALD fibroblasts. Redox imbalance appears to be the mechanism that initiates ER stress in X-ALD. Most importantly, we demonstrated that the bile acid tauroursodeoxycholate (TUDCA) abolishes UPR activation, which results in improvement of axonal degeneration and its associated locomotor impairment in Abcd1 - /Abcd2 -/- mice. Altogether, our preclinical data provide evidence for establishing the UPR as a key drug target in the pathogenesis cascade. Our study also highlights the potential role of TUDCA as a treatment for X-ALD and other axonopathies in which similar molecular mediators are implicated

Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations

Transcription disequilibria are characteristic of many neurodegenerative diseases. The activity-evoked transcription of immediate early genes (IEGs), important for neuronal plasticity, memory and behavior, is altered in CNS diseases and governed by epigenetic modulation. KDM1A, a histone 3 lysine 4 demethylase that forms part of transcription regulation complexes, has been implicated in the control of IEG transcription. Here we report the development of vafidemstat (ORY-2001), a brain penetrant inhibitor of KDM1A and MAOB. ORY-2001 efficiently inhibits brain KDM1A at doses suitable for long term treatment, and corrects memory deficit as assessed in the novel object recognition testing in the Senescence Accelerated Mouse Prone 8 (SAMP8) model for accelerated aging and Alzheimer's disease. Comparison with a selective KDM1A or MAOB inhibitor reveals that KDM1A inhibition is key for efficacy. ORY-2001 further corrects behavior alterations including aggression and social interaction deficits in SAMP8 mice and social avoidance in the rat rearing isolation model. ORY-2001 increases the responsiveness of IEGs, induces genes required for cognitive function and reduces a neuroinflammatory signature in SAMP8 mice. Multiple genes modulated by ORY-2001 are differentially expressed in Late Onset Alzheimer's Disease. Most strikingly, the amplifier of inflammation S100A9 is highly expressed in LOAD and in the hippocampus of SAMP8 mice, and down-regulated by ORY-2001. ORY-2001 is currently in multiple Phase IIa studies

Aberrant regulation of the GSK-3β/NRF2 axis unveils a novel therapy for adrenoleukodystrophy

The nuclear factor erythroid 2‐like 2 (NRF2) is the master regulator of endogenous antioxidant responses. Oxidative damage is a shared and early‐appearing feature in X‐linked adrenoleukodystrophy (X‐ALD) patients and the mouse model (Abcd1 null mouse). This rare neurometabolic disease is caused by the loss of function of the peroxisomal transporter ABCD1, leading to an accumulation of very long‐chain fatty acids and the induction of reactive oxygen species of mitochondrial origin. Here, we identify an impaired NRF2 response caused by aberrant activity of GSK‐3β. We find that GSK‐3β inhibitors can significantly reactivate the blunted NRF2 response in patients' fibroblasts. In the mouse models (Abcd1 − and Abcd1 −/Abcd2 −/− mice), oral administration of dimethyl fumarate (DMF/BG12/Tecfidera), an NRF2 activator in use for multiple sclerosis, normalized (i) mitochondrial depletion, (ii) bioenergetic failure, (iii) oxidative damage, and (iv) inflammation, highlighting an intricate cross‐talk governing energetic and redox homeostasis in X‐ALD. Importantly, DMF halted axonal degeneration and locomotor disability suggesting that therapies activating NRF2 hold therapeutic potential for X‐ALD and other axonopathies with impaired GSK‐3β/NRF2 axis. Keywords: adrenoleukodystrophy, dimethyl fumarate, GSK‐3, NRF2, oxidative stress Subject Categories: Genetics, Gene Therapy & Genetic Disease, Metabolism, Neuroscienc

Esca grapevine disease involves leaf hydraulic failure and represents a unique premature senescence process

Xylem anatomy may change in response to environmental or biotic stresses. Vascular occlusion, an anatomical modification of mature xylem, contributes to plant resistance and susceptibility to different stresses. In woody organs, xylem occlusions have been examined as part of the senescence process, but their presence and function in leaves remain obscure. In grapevine, many stresses are associated with premature leaf senescence inducing discolorations and scorched tissue in leaves. However, we still do not know whether the leaf senescence process follows the same sequence of physiological events and whether leaf xylem anatomy is affected in similar ways. In this study, we quantified vascular occlusions in midribs from leaves with symptoms of the grapevine disease esca, magnesium deficiency and autumn senescence. We found higher amounts of vascular occlusions in leaves with esca symptoms (in 27% of xylem vessels on average), whereas the leaves with other symptoms (as well as the asymptomatic controls) had far fewer occlusions (in 3% of vessels). Therefore, we assessed the relationship between xylem occlusions and esca leaf symptoms in four different countries (California in the USA, France, Italy and Spain) and eight different cultivars. We monitored the plants over the course of the growing season, confirming that vascular occlusions do not evolve with symptom age. Finally, we investigated the hydraulic integrity of leaf xylem vessels by optical visualization of embolism propagation during dehydration. We found that the occlusions lead to hydraulic dysfunction mainly in the peripheral veins compared with the midribs in esca symptomatic leaves. These results open new perspectives on the role of vascular occlusions during the leaf senescence process, highlighting the uniqueness of esca leaf symptoms and its consequence on leaf physiology