Pattern of degeneration of the rat inferior olivary complex after the early postnatal axotomy of the olivocerebellar projection

Neuronal death of inferior olivary neurons after early axotomy of the olivocerebellar tract was studied in newborn (Pl) hemicerebellectomized rats during the first six days after lesion. The degeneration of the inferior olive showed a topographic pattem from one (P2) to six days after axotomy (P7), after which this complex had almost completely disappeared. The first degenerative changes were observed in the principal olive (P2), while the media1 accessory olive was the later-degenerated area (P5). The analysis of these degenerative changes provides a reference for future experimental studies. Furthermore, the topographic study of the degenerative process demonstrated that: i) the most vulnerable neurons were dorsolaterally located, whereas the most resistant ones occupied the media1 aspect of the inferior olivary complex, ii) the comparison between the topographical arrangement of the inferior olivary neurons according to their birth dates, and the rate of degenerative changes observed after hemicerebellectomy, open the possibility that the neurona1 generation date and the response to the axotomy of the inferior olivary neurons could be related

HERC 1 Ubiquitin Ligase Mutation Affects Neocortical, CA3 Hippocampal and Spinal Cord Projection Neurons: An Ultrastructural Study

The spontaneous mutation tambaleante is caused by the Gly483Glu substitution in the highly conserved N terminal RCC1-like domain of the HERC1 protein, which leads to the increase of mutated protein levels responsible for cerebellar Purkinje cell death by autophagy. Until now, Purkinje cells have been the only central nervous neurons reported as being targeted by the mutation, and their degeneration elicits an ataxic syndrome in adult mutant mice. However, the ultrastructural analysis performed here demonstrates that signs of autophagy, such as autophagosomes, lysosomes, and altered mitochondria, are present in neocortical pyramidal, CA3 hippocampal pyramidal, and spinal cord motor neurons. The main difference is that the reduction in the number of neurons affected in the tarnbaleante mutation in the neocortex, the hippocampus, and the spinal cord is not so evident as the dramatic loss of cerebellar Purkinje cells. Interestingly, signs of autophagy are absent in both interneurons and neuroglia cells. Affected neurons have in common that they are projection neurons which receive strong and varied synaptic inputs, and possess the highest degree of neuronal activity. Therefore, because the integrity of the ubiquitin-proteasome system is essential for protein degradation and hence, for normal protein turnover, it could be hypothesized that the deleterious effects of the misrouting of these pathways would depend directly on the neuronal activity

El hándicap del transporte aéreo para el desarrollo inicial del turismo de masas en las Islas Canarias

Air transport has played a significant role in the development of mass tourism in the sixties and seventies, especially in a fragmented territory and away as the Canary Islands. Thus, without the advent of the jet engine to the Canary Islands, can’t understand the spectacular development of tourism in the islands during this period. Thus the main objective of this paper, is to show the decisive role of air transport for tourism development in the Canary Islands.El transporte aéreo, más aún en un territorio fragmentado y alejado como es el caso del Archipiélago canario, ha jugado un papel trascendental para el desarrollo del turismo de masas en los años sesenta y setenta. En efecto, sin la llegada del motor a reacción a Canarias, no se podría comprender el espectacular desarrollo turístico que las Islas experimentaron en este periodo, siendo el principal objetivo de este trabajo, abordar —aunque de forma sucinta—, este proceso absolutamente decisivo para las Islas

The HERC proteins and the nervous system

The HERC protein family is one of three subfamilies of Homologous to E6AP C-terminus (HECT) E3 ubiquitin ligases. Six HERC genes have been described in humans, two of which encode Large HERC proteins -HERC1 and HERC2- with molecular weights above 520 kDa that are constitutively expressed in the brain. There is a large body of evidence that mutations in these Large HERC genes produce clinical syndromes in which key neurodevelopmental events are altered, resulting in intellectual disability and other neurological disorders like epileptic seizures, dementia and/or signs of autism. In line with these consequences in humans, two mice carrying mutations in the Large HERC genes have been studied quite intensely: the tambaleante mutant for Herc1 and the Herc2+/530 mutant for Herc2. In both these mutant mice there are clear signs that autophagy is dysregulated, eliciting cerebellar Purkinje cell death and impairing motor control. The tambaleante mouse was the first of these mice to appear and is the best studied, in which the Herc1 mutation elicits: (i) delayed neural transmission in the peripheral nervous system; (ii) impaired learning, memory and motor control; and (iii) altered presynaptic membrane dynamics. In this review, we discuss the information currently available on HERC proteins in the nervous system and their biological activity, the dysregulation of which could explain certain neurodevelopmental syndromes and/or neurodegenerative diseases

The HERC1 ubiquitin ligase regulates presynaptic membrane dynamics of central synapses

HERC1 is a ubiquitin ligase protein, which, when mutated, induces several malformations and intellectual disability in humans. The animal model of HERC1 mutation is the mouse tambaleante characterized by: (1) overproduction of the protein; (2) cerebellar Purkinje cells death by autophagy; (3) dysregulation of autophagy in spinal cord motor neurons, and CA3 and neocortical pyramidal neurons; (4) impairment of associative learning, linked to altered spinogenesis and absence of LTP in the lateral amygdala; and, (5) motor impairment due to delayed action potential transmission, decrease synaptic transmission efficiency and altered myelination in the peripheral nervous system. To investigate the putative role of HERC1 in the presynaptic dynamics we have performed a series of experiments in cultured tambaleante hippocampal neurons by using transmission electron microscopy, FM1-43 destaining and immunocytochemistry. Our results show: (1) a decrease in the number of synaptic vesicles; (2) reduced active zones; (3) less clathrin immunoreactivity and less presynaptic endings over the hippocampal main dendritic trees; which contrast with (4) a greater number of endosomes and autophagosomes in the presynaptic endings of the tambaleante neurons relative to control ones. Altogether these results show an important role of HERC1 in the regulation of presynaptic membrane dynamics

SMN is physiologically down-regulated at wild-type motor nerve terminals but aggregates together with neurofilaments in SMA mouse models

Survival motor neuron (SMN) is an essential and ubiquitously expressed protein that participates in several aspects of RNA metabolism. SMN deficiency causes a devastating motor neuron disease called spinal muscular atrophy (SMA). SMN forms the core of a protein complex localized at the cytoplasm and nuclear gems and that catalyzes spliceosomal snRNP particle syn-thesis. In cultured motor neurons, SMN is also present in dendrites and axons, and forms part of the ribonucleoprotein transport granules implicated in mRNA trafficking and local translation. Nevertheless, the distribution, regulation, and role of SMN at the axons and presynaptic motor terminals in vivo are still unclear. By using conventional confocal microscopy and STED su-per-resolution nanoscopy, we found that SMN appears in the form of granules distributed along motor axons at nerve terminals. Our fluorescence in situ hybridization and electron microscopy studies also confirmed the presence of β-actin mRNA, ribosomes, and polysomes in the presynap-tic motor terminal, key elements of the protein synthesis machinery involved in local translation in this compartment. SMN granules co-localize with the microtubule-associated protein MAP1B and neurofilaments, suggesting that the cytoskeleton participates in transporting and positioning the granules. We also found that, while SMN granules are physiologically downregulated at the pre-synaptic element during the period of postnatal maturation in wild-type (non-transgenic) mice, they accumulate in areas of neurofilament aggregation in SMA mice, suggesting that the high ex-pression of SMN at the NMJ, together with the cytoskeletal defects, contribute to impairing the bi-directional traffic of proteins and organelles between the axon and the presynaptic terminal.This work was supported by the Spanish Agencia Estatal de Investigación (grant number:PID2019-110272RB-100/AEI/10.13039/501100011033 (LT), SMA Europe (LT), Ministerio de Ciencia eInnovación/FEDER (grant: PID2021-122785OB-I00) (JC)), the Deutsche Forschungsgemeinschaft (Se697/7-1 (MS)), and the Maratóde TV3 Foundation (202005 (JC and LT)

Track detection in railway sidings based on MEMS gyroscope sensors

The paper presents a two-step technique for real-time track detection in single-track railway sidings using low-cost MEMS gyroscopes. The objective is to reliably know the path the train has taken in a switch, diverted or main road, immediately after the train head leaves the switch. The signal delivered by the gyroscope is first processed by an adaptive low-pass filter that rejects noise and converts the temporal turn rate data in degree/second units into spatial turn rate data in degree/meter. The conversion is based on the travelled distance taken from odometer data. The filter is implemented to achieve a speed-dependent cut-off frequency to maximize the signal-to-noise ratio. Although direct comparison of the filtered turn rate signal with a predetermined threshold is possible, the paper shows that better detection performance can be achieved by processing the turn rate signal with a filter matched to the rail switch curvature parameters. Implementation aspects of the track detector have been optimized for real-time operation. The detector has been tested with both simulated data and real data acquired in railway campaigns.Peer ReviewedPostprint (published version

HERC1 ubiquitin ligase is required for hippocampal learning and memory

Mutations in the human HERC1 E3 ubiquitin ligase protein develop intellectual disability. The tambaleante (tbl) mouse carries a HERC1 mutation characterized by cerebellar ataxia due of adult cerebellar Purkinje cells death by extensive autophagy. Our previous studies demonstrated that both the neuromuscular junction and the peripheral nerve myelin sheaths are also affected in this mutant. Moreover, there are signs of dysregulated autophagy in the central nervous system in the tbl mouse, affecting spinal cord motor neurons, and pyramidal neurons of the neocortex and the hippocampal CA3 region. The tbl mutation affects associative learning, with absence of short- and long-term potentiation in the lateral amygdala, altered spinogenesis in their neurons, and a dramatic decrease in their glutamatergic input. To assess whether other brain areas engaged in learning processes might be affected by the tbl mutation, we have studied the tbl hippocampus using behavioral tests, ex vivo electrophysiological recordings, immunohistochemistry, the Golgi-Cox method and transmission electron microscopy. The tbl mice performed poorly in the novel-object recognition, T-maze and Morris water maze tests. In addition, there was a decrease in glutamatergic input while the GABAergic one remains unaltered in the hippocampal CA1 region of tbl mice, accompanied by changes in the dendritic spines, and signs of cellular damage. Moreover, the proportions of immature and mature neurons in the dentate gyrus of the tbl hippocampus differ relative to the control mice. Together, these observations demonstrate the important role of HERC1 in regulating synaptic activity during learning

The Ubiquitin Proteasome System in Neuromuscular Disorders: Moving Beyond Movement

Neuromuscular disorders (NMDs) affect 1 in 3000 people worldwide. There are more than 150 different types of NMDs, where the common feature is the loss of muscle strength. These disorders are classified according to their neuroanatomical location, as motor neuron diseases, peripheral nerve diseases, neuromuscular junction diseases, and muscle diseases. Over the years, numerous studies have pointed to protein homeostasis as a crucial factor in the development of these fatal diseases. The ubiquitin-proteasome system (UPS) plays a fundamental role in maintaining protein homeostasis, being involved in protein degradation, among other cellular functions. Through a cascade of enzymatic reactions, proteins are ubiquitinated, tagged, and translocated to the proteasome to be degraded. Within the ubiquitin system, we can find three main groups of enzymes: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-conjugating enzymes), and E3 (ubiquitin-protein ligases). Only the ubiquitinated proteins with specific chain linkages (such as K48) will be degraded by the UPS. In this review, we describe the relevance of this system in NMDs, summarizing the UPS proteins that have been involved in pathological conditions and neuromuscular disorders, such as Spinal Muscular Atrophy (SMA), Charcot-Marie-Tooth disease (CMT), or Duchenne Muscular Dystrophy (DMD), among others. A better knowledge of the processes involved in the maintenance of proteostasis may pave the way for future progress in neuromuscular disorder studies and treatments.Ministerio de Economía y Competitividad RTI2018-098645-B-10

Patient-Derived Cellular Models for Polytarget Precision Medicine in Pantothenate Kinase-Associated Neurodegeneration

The term neurodegeneration with brain iron accumulation (NBIA) brings together a broad set of progressive and disabling neurological genetic disorders in which iron is deposited preferentially in certain areas of the brain. Among NBIA disorders, the most frequent subtype is pantothenate kinase-associated neurodegeneration (PKAN) caused by pathologic variants in the PANK2 gene codifying the enzyme pantothenate kinase 2 (PANK2). To date, there are no effective treatments to stop the progression of these diseases. This review discusses the utility of patient-derived cell models as a valuable tool for the identification of pharmacological or natural compounds for implementing polytarget precision medicine in PKAN. Recently, several studies have described that PKAN patient-derived fibroblasts present the main pathological features associated with the disease including intracellular iron overload. Interestingly, treatment of mutant cell cultures with various supplements such as pantothenate, pantethine, vitamin E, omega 3, α-lipoic acid L-carnitine or thiamine, improved all pathophysiological alterations in PKAN fibroblasts with residual expression of the PANK2 enzyme. The information provided by pharmacological screenings in patient-derived cellular models can help optimize therapeutic strategies in individual PKAN patients.This work was supported by PI19/00377 and PI22/00142 grants, Instituto de Salud Carlos III, Spain and Fondo Europeo de Desarrollo Regional (FEDER-Unión Europea), Proyectos de Investigación de Excelencia de la Junta de Andalucía PY18-850 and UPO-FEDER 2018 (UPO-1380614).Peer reviewe