The Role of Chaperone-Mediated Autophagy in Tissue Homeostasis and Disease Pathogenesis.

Chaperone-mediated autophagy (CMA) is a selective proteolytic pathway in the lysosomes. Proteins are recognized one by one through the detection of a KFERQ motif or, at least, a KFERQ-like motif, by a heat shock cognate protein 70 (Hsc70), a molecular chaperone. CMA substrates are recognized and delivered to a lysosomal CMA receptor, lysosome-associated membrane protein 2A (LAMP-2A), the only limiting component of this pathway, and transported to the lysosomal lumen with the help of another resident chaperone HSp90. Since approximately 75% of proteins are reported to have canonical, phosphorylation-generated, or acetylation-generated KFERQ motifs, CMA maintains intracellular protein homeostasis and regulates specific functions in the cells in different tissues. CMA also regulates physiologic functions in different organs, and is then implicated in disease pathogenesis related to aging, cancer, and the central nervous and immune systems. In this minireview, we have summarized the most important findings on the role of CMA in tissue homeostasis and disease pathogenesis, updating the recent advances for this Special Issue.

Investigating the impact of physical activity on mitochondrial function in Parkinson's disease (PARKEX): Study protocol for A randomized controlled clinical trial.

Parkinson's disease (PD) is characterized by the progressive dopaminergic neuron degeneration, resulting in striatal dopamine deficiency. Mitochondrial dysfunction and oxidative stress are associated with PD pathogenesis. Physical activity (PA) has been shown to ameliorate neurological impairments and to impede age-related neuronal loss. In addition, skin fibroblasts have been identified as surrogate indicators of pathogenic processes correlating with clinical measures. The PARKEX study aims to compare the effects of two different PA programs, analyzing the impact on mitochondrial function in patients' skin fibroblasts as biomarkers for disease status and metabolic improvement. Early-stage PD patients (n = 24, H&Y stage I to III) will be randomized into three age- and sex-matched groups. Group 1 (n = 8) will undergo basic physical training (BPT) emphasizing strength and resistance. Group 2 (n = 8) will undergo BPT combined with functional exercises (BPTFE), targeting the sensorimotor pathways that are most affected in PD (proprioception-balance-coordination) together with cognitive and motor training (Dual task training). Group 3 (n = 8) will serve as control (sedentary group; Sed). Participants will perform three sessions per week for 12 weeks. Assessment of motor function, quality of life, sleep quality, cognitive aspects and humor will be conducted pre- and post-intervention. Patient skin fibroblasts will be collected before and after the intervention and characterized in terms of metabolic remodeling and mitochondrial bioenergetics. Ethical approval has been given to commence this study. This trial is registered at clinicaltrials.gov (NCT05963425). Trial registration. https://classic.clinicaltrials.gov/ct2/history/NCT05963425.

Relationship between Learning English as a Foreign Language and the Executive Attention Profile in Spanish Schoolchildren / [Relación entre el aprendizaje del inglés como lengua extranjera y el perfil ejecutivo atencional en escolares españoles]

Executive functions are established as vital in learning, as well as in the development of psycholinguistic skills crucial to learning a second language. The present study analyzes relationships between variables linked to executive functioning and to academic achievement in English as a foreign language (EFL). The participants were 519 primary school students between the ages of 10 and 12. The results show a tendency to greater sustained and selective attention and consequently better attention control and concentration on task when academic achievement in English was higher. Our discriminant analysis verifies that sustained and selective attention, attention deficit, and concentration on task explain and predict group membership in EFL achievement groups (low, medium, and high achievement). It is important to plan activities to develop executive functioning, alongside the regular curriculum content, in order to improve learning and acquisition of psycholinguistic skills, the foundation for bilingualism or second-language learning.(AU)

Se constata la importancia de las funciones ejecutivas en el aprendizaje, así como en el desarrollo de habilidades psicolingüísticas cruciales para aprender un segundo idioma. En este estudio se analizan las relaciones entre variables vinculadas al funcionamiento ejecutiv y al rendimiento académico en lengua inglesa. Participaron 519 estudiantes de primaria de edades comprendidas entre 10 y 12 años. Los resultados evidencian la tendencia a una mayor atención sostenida y selectiva y en consecuencia un mejor control atencional y de concentración en la tarea cuando es mayor el rendimiento académico en lengua inglesa; el análisis discriminante efectuado verifica el carácter explicativo y predictivo de la atención sostenida y selectiva, el déficit atencional y la concentración en la tarea en la pertenencia de cada estudiante a los grupos (bajo, medio y alto) de rendimiento en dicha asignatura. Se constata la importancia de programar actuaciones para el desarrollo del funcionamiento ejecutivo en paralelo a las propiamente curriculares, para mejorar el aprendizaje y la adquisición de habilidades psicolingüísticas, base del bilingüismo o del aprendizaje de un segundo idioma.(AU)

The Consequences of GBA Deficiency in the Autophagy-Lysosome System in Parkinson's Disease Associated with GBA.

GBA gene variants were the first genetic risk factor for Parkinson's disease. GBA encodes the lysosomal enzyme glucocerebrosidase (GBA), which is involved in sphingolipid metabolism. GBA exhibits a complex physiological function that includes not only the degradation of its substrate glucosylceramide but also the metabolism of other sphingolipids and additional lipids such as cholesterol, particularly when glucocerebrosidase activity is deficient. In the context of Parkinson's disease associated with GBA, the loss of GBA activity has been associated with the accumulation of α-synuclein species. In recent years, several hypotheses have proposed alternative and complementary pathological mechanisms to explain why lysosomal enzyme mutations lead to α-synuclein accumulation and become important risk factors in Parkinson's disease etiology. Classically, loss of GBA activity has been linked to a dysfunctional autophagy-lysosome system and to a subsequent decrease in autophagy-dependent α-synuclein turnover; however, several other pathological mechanisms underlying GBA-associated parkinsonism have been proposed. This review summarizes and discusses the different hypotheses with a special focus on autophagy-dependent mechanisms, as well as autophagy-independent mechanisms, where the role of other players such as sphingolipids, cholesterol and other GBA-related proteins make important contributions to Parkinson's disease pathogenesis.

Lysosomal lipid alterations caused by glucocerebrosidase deficiency promote lysosomal dysfunction, chaperone-mediated-autophagy deficiency, and alpha-synuclein pathology.

Mutations in the GBA gene that encodes the lysosomal enzyme ß-glucocerebrosidase (GCase) are a major genetic risk factor for Parkinson's disease (PD). In this study, we generated a set of differentiated and stable human dopaminergic cell lines that express the two most prevalent GBA mutations as well as GBA knockout cell lines as a in vitro disease modeling system to study the relationship between mutant GBA and the abnormal accumulation of α-synuclein. We performed a deep analysis of the consequences triggered by the presence of mutant GBA protein and the loss of GCase activity in different cellular compartments, focusing primarily on the lysosomal compartment, and analyzed in detail the lysosomal activity, composition, and integrity. The loss of GCase activity generates extensive lysosomal dysfunction, promoting the loss of activity of other lysosomal enzymes, affecting lysosomal membrane stability, promoting intralysosomal pH changes, and favoring the intralysosomal accumulation of sphingolipids and cholesterol. These local events, occurring only at a subcellular level, lead to an impairment of autophagy pathways, particularly chaperone-mediated autophagy, the main α-synuclein degradative pathway. The findings of this study highlighted the role of lysosomal function and lipid metabolism in PD and allowed us to describe a molecular mechanism to understand how mutations in GBA can contribute to an abnormal accumulation of different α-synuclein neurotoxic species in PD pathology.

Coordination of mitochondrial and lysosomal homeostasis mitigates inflammation and muscle atrophy during aging.

Sarcopenia is one of the main factors contributing to the disability of aged people. Among the possible molecular determinants of sarcopenia, increasing evidences suggest that chronic inflammation contributes to its development. However, a key unresolved question is the nature of the factors that drive inflammation during aging and that participate in the development of sarcopenia. In this regard, mitochondrial dysfunction and alterations in mitophagy induce inflammatory responses in a wide range of cells and tissues. However, whether accumulation of damaged mitochondria (MIT) in muscle could trigger inflammation in the context of aging is still unknown. Here, we demonstrate that BCL2 interacting protein 3 (BNIP3) plays a key role in the control of mitochondrial and lysosomal homeostasis, and mitigates muscle inflammation and atrophy during aging. We show that muscle BNIP3 expression increases during aging in mice and in some humans. BNIP3 deficiency alters mitochondrial function, decreases mitophagic flux and, surprisingly, induces lysosomal dysfunction, leading to an upregulation of Toll-like receptor 9 (TLR9)-dependent inflammation and activation of the NLRP3 (nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)-, and pyrin domain-containing protein 3) inflammasome in muscle cells and mouse muscle. Importantly, downregulation of muscle BNIP3 in aged mice exacerbates inflammation and muscle atrophy, and high BNIP3 expression in aged human subjects associates with a low inflammatory profile, suggesting a protective role for BNIP3 against age-induced muscle inflammation in mice and humans. Taken together, our data allow us to propose a new adaptive mechanism involving the mitophagy protein BNIP3, which links mitochondrial and lysosomal homeostasis with inflammation and is key to maintaining muscle health during aging.

Autophagy and the hallmarks of aging.

Autophagy, an essential cellular process that mediates degradation of proteins and organelles in lysosomes, has been tightly linked to cellular quality control for its role as part of the proteostasis network. The current interest in identifying the cellular and molecular determinants of aging, has highlighted the important contribution of malfunctioning of autophagy with age to the loss of proteostasis that characterizes all old organisms. However, the diversity of cellular functions of the different types of autophagy and the often reciprocal interactions of autophagy with other determinants of aging, is placing autophagy at the center of the aging process. In this work, we summarize evidence for the contribution of autophagy to health- and lifespan and provide examples of the bidirectional interplay between autophagic pathways and several of the so-called hallmarks of aging. This central role of autophagy in aging, and the dependence on autophagy of many geroprotective interventions, has motivated a search for direct modulators of autophagy that could be used to slow aging and extend healthspan. Here, we review some of those ongoing therapeutic efforts and comment on the potential of targeting autophagy in aging.

Mutant HTT (huntingtin) impairs mitophagy in a cellular model of Huntington disease.

The precise degradation of dysfunctional mitochondria by mitophagy is essential for maintaining neuronal homeostasis. HTT (huntingtin) can interact with numerous other proteins and thereby perform multiple biological functions within the cell. In this study, we investigated the role of HTT during mitophagy and analyzed the impact of the expansion of its polyglutamine (polyQ) tract. HTT is involved in different mitophagy steps, promoting the physical proximity of different protein complexes during the initiation of mitophagy and recruiting mitophagy receptors essential for promoting the interaction between damaged mitochondria and the nascent autophagosome. The presence of the polyQ tract in mutant HTT affects the formation of these protein complexes and determines the negative consequences of mutant HTT on mitophagy, leading to the accumulation of damaged mitochondria and an increase in oxidative stress. These outcomes contribute to general mitochondrial dysfunction and neurodegeneration in Huntington disease.Abbreviations: AMPK: AMP-activated protein kinase; ATG13: autophagy related 13; BECN1: beclin 1, autophagy related; BNIP3: BCL2/adenovirus E1B interacting protein 3; BNIP3L/Nix: BCL2/adenovirus E1B interacting protein 3-like; CCCP: carbonyl cyanide 3-chlorophenyl hydrazone; DMEM: Dulbecco's modified eagle medium; EDTA: ethylene-diamine-tetra-acetic acid; EGFP: enhanced green fluorescent protein; EGTA: ethylene glycol bis(2-aminoethyl ether)tetraacetic acid; FUNDC1: FUN14 domain containing 1; HD: Huntington disease; HRP: horseradish peroxidase; HTT: huntingtin; LC3-II: lipidated form of MAP1LC3/LC3; mtDNA: mitochondrial deoxyribonucleic acid; MTDR: MitoTracker Deep Red; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; NBR1: NBR1, autophagy cargo receptor; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; OCR: oxygen consumption rate; OPTN: optineurin; OXPHOS: oxidative phosphorylation; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4/VPS15: phosphoinositide-3-kinase regulatory subunit 4; PINK1: PTEN induced putative kinase 1; PLA: proximity ligation assay; PMSF: phenylmethylsulfonyl fluoride; polyQ: polyglutamine; PtdIns3K: phosphatidylinositol 3-kinase; ROS: reactive oxygen species; Rot: rotenone; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SEM: standard error of the mean; SQSTM1/p62: sequestosome 1; TMRM: tetramethylrhodamine methyl ester; UB: ubiquitin; ULK1: unc-51 like kinase 1.

Satisfacción vital y sintomatología prefrontal como predictores de la atención plena disposicional en la mujer rural / Life satisfaction and prefrontal symptomatology as predictors of dispositional mindfulness in rural women

Durante los últimos años han aumentado las investigaciones sobre atención plena (mindfulness) tanto como estado o como rasgo disposicional y su relación con diferentes variables relacionadas con la salud y bienestar de la persona. El objetivo de este trabajo fue analizar la relación y el carácter predictivo de la satisfacción vital y sintomatología prefrontal en la atención plena disposicional en la mujer rural. Participaron 239 mujeres de distintas localidades rurales de España de entre 17 y 87 años de edad (M= 56,13; DT= 14,98). Los resultados confirman el carácter predictivo de niveles altos de satisfacción vital y bajos en sintomatología prefrontal y problemas en control ejecutivo respecto a un mayor nivel de atención plena disposicional de las mujeres evaluadas. Tras discutir los hallazgos obtenidos, que derivan consecuencias clínicas y sociosanitarias, proponemos seguir profundizando en esta línea específica de investigación dados los beneficios probados de la atención plena en el bienestar general de la persona, actuando como factor protector de la salud mental, física y emocional (AU)

In recent years there has been an increase in research on mindfulness as a state or dispositional trait, and on its relationship with different variables pertaining to the health and well-being of the individual. The objective of this study was to analyze the relationship and the predictive character of life satisfaction and prefrontal symptoms in dispositional mindfulness levels in rural women. The participants were 239 women from different rural communities in Spain, between the ages of 17 and 87 years (M= 56.13, SD= 4.98). The results confirmed that high levels of life satisfaction and low levels of prefrontal symptoms and executive control problems were predictive of a higher level of dispositional mindfulness in the women evaluated. After discussing our findings with their clinical and socio health implications, we recommend further inquiry into this specific line o research, given the proven benefits of mindfulness for general personal well-being, where it acts as a protective factor for mental, physical and emotional health (AU)

Ajuste personal y conductas disruptivas en alumnado de primaria / Personal Adjustment and Disruptive Behaviors in Primary School Students

Resumen. Objetivo. Estudiar las relaciones entre variables de ajuste personal y las conductas disruptivas en un grupo de 136 alumnos y alumnas de primaria de entre 9 y 12 años. Método. Estudio de campo observacional, de metodología no experimental y transversal. Se utilizaron varios cuestionarios para medir la autoestima, la personalidad, el estrés y las competencias emocionales de los y las estudiantes, así como un cuestionario ad hoc elaborado para el registro de las conductas disruptivas. Resultados. Los resultados indican relaciones significativas positivas entre conductas disruptivas y estrés escolar, así como negativas con autoestima, estabilidad, competencia y comprensión emocional. Las diferencias son significativas según el género, manifestándose las conductas inadecuadas en menor medida en el caso de las niñas.

Abstract. Objective. This study analyses the relationships between personal adjustment and disruptive behaviors in a group of 136 primary school students between the ages of 9 and 12. Method. This field observation study used a non-experimental, cross-sectional methodology. Several questionnaires were used to measure students' self-esteem, personality, stress, and emotional competencies. Moreover, an ad hoc questionnaire was created to record disruptive behaviors. Results. The results indicate significant positive relationships between disruptive behaviors and school stress, as well as negative ones with self-esteem, stability, competence, and emotional understanding. The differences are significant according to gender, with inappropriate behaviors manifesting to a lesser extent in the case of girls.

The Emerging Role of the Lysosome in Parkinson's Disease.

Lysosomal function has a central role in maintaining neuronal homeostasis, and, accordingly, lysosomal dysfunction has been linked to neurodegeneration and particularly to Parkinson's disease (PD). Lysosomes are the converging step where the substrates delivered by autophagy and endocytosis are degraded in order to recycle their primary components to rebuild new macromolecules. Genetic studies have revealed the important link between the lysosomal function and PD; several of the autosomal dominant and recessive genes associated with PD as well as several genetic risk factors encode for lysosomal, autophagic, and endosomal proteins. Mutations in these PD-associated genes can cause lysosomal dysfunction, and since α-synuclein degradation is mostly lysosomal-dependent, among other consequences, lysosomal impairment can affect α-synuclein turnover, contributing to increase its intracellular levels and therefore promoting its accumulation and aggregation. Recent studies have also highlighted the bidirectional link between Parkinson's disease and lysosomal storage diseases (LSD); evidence includes the presence of α-synuclein inclusions in the brain regions of patients with LSD and the identification of several lysosomal genes involved in LSD as genetic risk factors to develop PD.

Impaired proteasome activity and neurodegeneration with brain iron accumulation in FBXO7 defect.

FBXO7 is implicated in the ubiquitin-proteasome system and parkin-mediated mitophagy. FBXO7defects cause a levodopa-responsive parkinsonian-pyramidal syndrome(PPS). METHODS: We investigated the disease molecular bases in a child with PPS and brain iron accumulation. RESULTS: A novel homozygous c.368C>G (p.S123*) FBXO7 mutation was identified in a child with spastic paraplegia, epilepsy, cerebellar degeneration, levodopa nonresponsive parkinsonism, and brain iron deposition. Patient's fibroblasts assays demonstrated an absence of FBXO7 RNA expression leading to impaired proteasome degradation and accumulation of poly-ubiquitinated proteins. CONCLUSION: This novel FBXO7 phenotype associated with impaired proteasome activity overlaps with neurodegeneration with brain iron accumulation disorders.

Sex-dependent calcium hyperactivity due to lysosomal-related dysfunction in astrocytes from APOE4 versus APOE3 gene targeted replacement mice.

BACKGROUND: The apolipoprotein E (APOE) gene exists in three isoforms in humans: APOE2, APOE3 and APOE4. APOE4 causes structural and functional alterations in normal brains, and is the strongest genetic risk factor of the sporadic form of Alzheimer's disease (LOAD). Research on APOE4 has mainly focused on the neuronal damage caused by defective cholesterol transport and exacerbated amyloid-ß and Tau pathology. The impact of APOE4 on non-neuronal cell functions has been overlooked. Astrocytes, the main producers of ApoE in the healthy brain, are building blocks of neural circuits, and Ca2+ signaling is the basis of their excitability. Because APOE4 modifies membrane-lipid composition, and lipids regulate Ca2+ channels, we determined whether APOE4 dysregulates Ca2+signaling in astrocytes. METHODS: Ca2+ signals were recorded in astrocytes in hippocampal slices from APOE3 and APOE4 gene targeted replacement male and female mice using Ca2+ imaging. Mechanistic analyses were performed in immortalized astrocytes. Ca2+ fluxes were examined with pharmacological tools and Ca2+ probes. APOE3 and APOE4 expression was manipulated with GFP-APOE vectors and APOE siRNA. Lipidomics of lysosomal and whole-membranes were also performed. RESULTS: We found potentiation of ATP-elicited Ca2+responses in APOE4 versus APOE3 astrocytes in male, but not female, mice. The immortalized astrocytes modeled the male response, and showed that Ca2+ hyperactivity associated with APOE4 is caused by dysregulation of Ca2+ handling in lysosomal-enriched acidic stores, and is reversed by the expression of APOE3, but not of APOE4, pointing to loss of function due to APOE4 malfunction. Moreover, immortalized APOE4 astrocytes are refractory to control of Ca2+ fluxes by extracellular lipids, and present distinct lipid composition in lysosomal and plasma membranes. CONCLUSIONS: Immortalized APOE4 versus APOE3 astrocytes present: increased Ca2+ excitability due to lysosome dysregulation, altered membrane lipidomes and intracellular cholesterol distribution, and impaired modulation of Ca2+ responses upon changes in extracellular lipids. Ca2+ hyperactivity associated with APOE4 is found in astrocytes from male, but not female, targeted replacement mice. The study suggests that, independently of Aß and Tau pathologies, altered astrocyte excitability might contribute to neural-circuit hyperactivity depending on APOE allele, sex and lipids, and supports lysosome-targeted therapies to rescue APOE4 phenotypes in LOAD.

Novel Therapeutic Approach to Induce Autophagy in a Drosophila Model for Huntington's Disease.

Autophagy induction is an attractive therapeutic approach to ameliorate aggregate accumulation in many neurodegenerative diseases. In Huntington's disease (HD) in vivo models, a number of genetic and pharmacological mechanisms aimed to induce autophagy have been successfully tested [1], demonstrating the role of autophagy in promoting the elimination of mutant huntingtin (mHTT) aggregates and its neuroprotective effect. In their recent report in Cells, Vernizzi and colleagues [2] presented a totally new mechanism to induce autophagy, promote the elimination of mHTT aggregates, and ultimately achieve neuroprotection. This novel therapy is based on the overexpression of glutamine synthetase 1 (GS1), an enzyme that catalyzes the synthesis of L-glutamine from L-glutamate as part of the glutamate glutamine cycle (GGC), a physiological process between glia and neurons that controls glutamate homeostasis [3].[...].

Rendimiento Académico según Distintos Niveles de Funcionalidad Ejecutiva y de Estrés Infantil Percibido / Academic performance in relation to different levels of executive functioning and perceived childhood stress

Dentro de la multiplicidad de variables que influyen en el aprendizaje y en el rendimiento académico, las funciones ejecutivas y el estrés cotidiano se consideran esenciales en la investigación actual. Este trabajo tiene como objetivo general estudiar las relaciones entre variables vinculadas a las funciones ejecutivas, el estrés infantil y el rendimiento académico obteniendo información de 649 estudiantes de Educación Primaria. Se conforman tres grupos (bajo-medio-alto) según la funcionalidad ejecutiva y el estrés infantil, cuyos resultados evidencian diferencias significativas en rendimiento académico entre los grupos alto y medio-bajo, tanto en el caso de las funciones ejecutivas como del estrés global. Se concluye reivindicando programas para mejorar el funcionamiento ejecutivo, junto con intervenciones psicoeducativas para la adquisición y el desarrollo de estrategias de afrontamiento para manejar situaciones estresantes cuyo fin último sea mejorar el rendimiento académico

While there are multiple variables that influence learning and academic achievement, current research considers executive functions and daily stress to be essential. The general aim of this study was to examine how variables pertaining to executive functions and childhood stress relate to academic achievement, obtaining information from 649 primary school students for this purpose. Three groups (low-medium-high) were formed according to levels of executive functioning and levels of childhood stress. The results showed significant differences in academic achievement between high and medium-low groups, both in executive functions and in overall stress. We conclude with a call for programs that improve executive functioning, as well as psychoeducational interventions that promote acquisition and development of coping strategies to manage stressful situations, with the ultimate purpose of improving academic achievement

Estrés cotidiano infantil y factores ligados al aprendizaje escolar como predictores del rendimiento académico / Daily childhood stress and factors related to academic learning as predictors of academic achievement

ANTECEDENTES Y OBJETIVOS: Dentro del amplio espectro de variables que influyen en el aprendizaje y, en consecuencia, en el rendimiento académico, cobran especial relevancia las afectivomotivacionales relacionadas con el estrés cotidiano. El objetivo general de este estudio es analizar las asociaciones entre el estrés cotidiano infantil, las estrategias de aprendizaje y la motivación académica, analizando las diferencias y su carácter predictivo en función de 3 grupos de rendimiento (bajo, medio y alto). MÉTODO: Estudio transversal, de metodología no experimental, descriptivo, correlacional, inferencial y multivariado. Participaron 535 estudiantes de tercer ciclo de Educación Primaria de Cantabria de edades comprendidas entre los 9 y los 12 años (M = 10.72; DT = .67), quienes cumplimentaron el Inventario de Estrés Cotidiano Infantil y el Diagnóstico Integral del Estudio, recogiéndose además las calificaciones escolares en Lengua Castellana, Inglés y Matemáticas. RESULTADOS: Los resultados muestran relaciones positivas y significativas entre todas las variables vinculadas al aprendizaje y el rendimiento académico, al tiempo negativas y significativas entre todas ellas y el estrés cotidiano global (así como en los ámbitos salud, escolar y familiar). El análisis multivariado discriminante explica el carácter predictivo de las estrategias complementarias, el estrés escolar, la actitud hacia el estudio y el autoconcepto según distintos niveles de rendimiento académico general. CONCLUSIONES: Se reclaman intervenciones en estrategias autorreguladoras del aprendizaje que sirvan como medida preventiva y de desarrollo de estrategias de afrontamiento ante situaciones estresantes dentro y fuera del ámbito educativo

BACKGROUND AND OBJECTIVES: Within the broad spectrum of variables that influence learning and consequently academic achievement, affective-motivational factors related to daily stress are particularly important. The aim of this study was to analyze associations between daily childhood stress, learning strategies and academic motivation, by analyzing how they differ across 3 achievement groups (low, medium and high), and the predictive-ability of these groupings. METHOD: Non-experimental methodology in a cross-sectional, descriptive, correlational, inferential and multivariate study. A total of 535 primary school students from Cantabria, Spain, aged 9 to 12 (M = 10.72; SD = 0.67), participated in the study. They completed the Inventario de Estrés Cotidiano Infantil [Children's Daily Stress Inventory] and the Diagnóstico Integral del Estudio [Comprehensive Diagnosis of Study], and their school grades were recorded for the subjects of Language Arts, English as a Foreign Language, and Mathematics. RESULTS: The results showed positive, significant relationships between all the variables pertaining to learning and academic achievement; each of these variables, in turn, had negative, significant relationships with global daily stress (as well as with health, school and family stress). The multivariate discriminant analysis explained the predictive role of complementary strategies, school stress, attitude toward study and self-concept, in different levels of general academic achievement. CONCLUSIONS: There is a need for interventions in self-regulated learning strategies that would serve as a preventive measure, and in development of coping strategies for stressful situations inside and outside the educational context

Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson's disease pathogenesis.

In Parkinson's disease (PD) there is a selective degeneration of neuromelanin-containing neurons, especially substantia nigra dopaminergic neurons. In humans, neuromelanin accumulates with age, the latter being the main risk factor for PD. The contribution of neuromelanin to PD pathogenesis remains unknown because, unlike humans, common laboratory animals lack neuromelanin. Synthesis of peripheral melanins is mediated by tyrosinase, an enzyme also present at low levels in the brain. Here we report that overexpression of human tyrosinase in rat substantia nigra results in age-dependent production of human-like neuromelanin within nigral dopaminergic neurons, up to levels reached in elderly humans. In these animals, intracellular neuromelanin accumulation above a specific threshold is associated to an age-dependent PD phenotype, including hypokinesia, Lewy body-like formation and nigrostriatal neurodegeneration. Enhancing lysosomal proteostasis reduces intracellular neuromelanin and prevents neurodegeneration in tyrosinase-overexpressing animals. Our results suggest that intracellular neuromelanin levels may set the threshold for the initiation of PD.

Glucocerebrosidase deficiency in dopaminergic neurons induces microglial activation without neurodegeneration.

Mutations in the GBA1 gene encoding the lysosomal enzyme glucocerebrosidase (GBA1) are important risk factors for Parkinson's disease (PD). In vitro, altered GBA1 activity promotes alpha-synuclein accumulation whereas elevated levels of alpha-synuclein compromise GBA1 function, thus supporting a pathogenic mechanism in PD. However, the mechanisms by which GBA1 deficiency is linked to increased risk of PD remain elusive, partially because of lack of aged models of GBA1 deficiency. As knocking-out GBA1 in the entire brain induces massive neurodegeneration and early death, we generated a mouse model of GBA1 deficiency amenable to investigate the long-term consequences of compromised GBA1 function in dopaminergic neurons. DAT-Cre and GBA1-floxed mice were bred to obtain selective homozygous disruption of GBA1 in midbrain dopamine neurons (DAT-GBA1-KO). Mice were followed for motor function, neuronal survival, alpha-synuclein phosphorylation and glial activation. Susceptibility to nigral viral vector-mediated overexpression of mutated (A53T) alpha-synuclein was assessed. Despite loss of GBA1 and substrate accumulation, DAT-GBA1-KO mice displayed normal motor performances and preserved dopaminergic neurons despite robust microglial activation in the substantia nigra, without accumulation of endogenous alpha-synuclein with respect to wild-type mice. Lysosomal function was only marginally affected. Screening of micro-RNAs linked to the regulation of GBA1, alpha-synuclein or neuroinflammation did not reveal significant alterations. Viral-mediated overexpression of A53T-alpha-synuclein yielded similar neurodegeneration in DAT-GBA1-KO mice and wild-type mice. These results indicate that loss of GBA1 function in mouse dopaminergic neurons is not critical for alpha-synuclein accumulation or neurodegeneration and suggest the involvement of GBA1 deficiency in other cell types as a potential mechanism.

Neuronal Mitophagy in Neurodegenerative Diseases.

Neuronal homeostasis depends on the proper functioning of different quality control systems. All intracellular components are subjected to continuous turnover through the coordinated synthesis, degradation and recycling of their constituent elements. Autophagy is the catabolic mechanism by which intracellular cytosolic components, including proteins, organelles, aggregates and any other intracellular materials, are delivered to lysosomes for degradation. Among the different types of selective autophagy described to date, the process of mitophagy involves the selective autophagic degradation of mitochondria. In this way, mitophagy is responsible for basal mitochondrial turnover, but can also be induced under certain physiological or pathogenic conditions to eliminate unwanted or damaged mitochondria. Dysfunctional cellular proteolytic systems have been linked extensively to neurodegenerative diseases (ND) like Alzheimer's disease (AD), Parkinson's disease (PD), or Huntington's disease (HD), with autophagic failure being one of the main factors contributing to neuronal cell death in these diseases. Neurons are particularly vulnerable to autophagic impairment as well as to mitochondrial dysfunction, due mostly to their particular high energy dependence and to their post-mitotic nature. The accurate and proper degradation of dysfunctional mitochondria by mitophagy is essential for maintaining control over mitochondrial quality and quantity in neurons. In this report, I will review the role of mitophagy in neuronal homeostasis and the consequences of its dysfunction in ND.