De novo variants in DENND5B cause a neurodevelopmental disorder.

The Rab family of guanosine triphosphatases (GTPases) includes key regulators of intracellular transport and membrane trafficking targeting specific steps in exocytic, endocytic, and recycling pathways. DENND5B (Rab6-interacting Protein 1B-like protein, R6IP1B) is the longest isoform of DENND5, an evolutionarily conserved DENN domain-containing guanine nucleotide exchange factor (GEF) that is highly expressed in the brain. Through exome sequencing and international matchmaking platforms, we identified five de novo variants in DENND5B in a cohort of five unrelated individuals with neurodevelopmental phenotypes featuring cognitive impairment, dysmorphism, abnormal behavior, variable epilepsy, white matter abnormalities, and cortical gyration defects. We used biochemical assays and confocal microscopy to assess the impact of DENND5B variants on protein accumulation and distribution. Then, exploiting fluorescent lipid cargoes coupled to high-content imaging and analysis in living cells, we investigated whether DENND5B variants affected the dynamics of vesicle-mediated intracellular transport of specific cargoes. We further generated an in silico model to investigate the consequences of DENND5B variants on the DENND5B-RAB39A interaction. Biochemical analysis showed decreased protein levels of DENND5B mutants in various cell types. Functional investigation of DENND5B variants revealed defective intracellular vesicle trafficking, with significant impairment of lipid uptake and distribution. Although none of the variants affected the DENND5B-RAB39A interface, all were predicted to disrupt protein folding. Overall, our findings indicate that DENND5B variants perturb intracellular membrane trafficking pathways and cause a complex neurodevelopmental syndrome with variable epilepsy and white matter involvement.

Possible incomplete penetrance of Xq28 int22h-1/int22h-2 duplication.

Xq28 int22h-1/int22h-2 duplication is the result of non-allelic homologous recombination between int22h-1/int22h-2 repeats separated by 0.5 Mb. It is responsible for a syndromic form of intellectual disability (ID), with recurrent infections and atopic diseases. Minor defects, nonspecific facial dysmorphic features, and overweight have also been described. Half of female carriers have been reported with ID, whereas all reported evaluated born males present mild to moderate ID, suggesting complete penetrance. We collected data on 15 families from eight university hospitals. Among them, 40 patients, 21 females (one fetus), and 19 males (two fetuses), were carriers of typical or atypical Xq28 int22h-1/int22h-2 duplication. Twenty-one individuals were considered asymptomatic (16 females and 5 males), without significantly higher rate of recurrent infections, atopia, overweight, or facial dysmorphism. Approximately 67% live-born males and 23% live-born female carriers of the typical duplication did not have obvious signs of intellectual disability, suggesting previously undescribed incomplete penetrance or low expression in certain carriers. The possibility of a second-hit or modifying factors to this possible susceptibility locus is yet to be studied but a possible observational bias should be considered in assessing such challenging X-chromosome copy number gains. Additional segregation studies should help to quantify this newly described incomplete penetrance.

Parkinson's Disease Gene Screening in Familial Cases from Central and South America.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease following Alzheimer's disease. Nearly 30 causative genes have been identified for PD and related disorders. However, most of these genes were identified in European-derived families, and little is known about their role in Latin American populations. OBJECTIVES: Our goal was to assess the spectrum and frequency of pathogenic variants in known PD genes in familial PD patients from Latin America. METHODS: We selected 335 PD patients with a family history of PD from the Latin American Research Consortium on the Genetics of PD. We capture-sequenced the coding regions of 26 genes related to neurodegenerative parkinsonism. Of the 335 PD patients, 324 had sufficient sequencing coverage to be analyzed. RESULTS: We identified pathogenic variants in 41 individuals (12.7%) in FBXO7, GCH1, LRRK2, PARK7, PINK1, PLA2G6, PRKN, SNCA, and TARDBP, GBA1 risk variants in 25 individuals (7.7%), and variants of uncertain significance in another 24 individuals (7.4%) in ATP13A2, ATP1A3, DNAJC13, DNAJC6, GBA1, LRKK2, PINK1, VPS13C, and VPS35. Of the 70 unique variants identified, 19 were more frequent in Latin Americans than in any other population. CONCLUSIONS: This is the first screening of known PD genes in a large cohort of patients with familial PD from Latin America. There were substantial differences in the spectrum of variants observed in comparison to previous findings from PD families of European origin. Our data provide further evidence that differences exist between the genetic architecture of PD in Latinos and European-derived populations. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

3q29 duplications: A cohort of 46 patients and a literature review.

Duplications of the 3q29 cytoband are rare chromosomal copy number variations (CNVs) (overlapping or recurrent ~1.6 Mb 3q29 duplications). They have been associated with highly variable neurodevelopmental disorders (NDDs) with various associated features or reported as a susceptibility factor to the development of learning disabilities and neuropsychiatric disorders. The smallest region of overlap and the phenotype of 3q29 duplications remain uncertain. We here report a French cohort of 31 families with a 3q29 duplication identified by chromosomal microarray analysis (CMA), including 14 recurrent 1.6 Mb duplications, eight overlapping duplications (>1 Mb), and nine small duplications (<1 Mb). Additional genetic findings that may be involved in the phenotype were identified in 11 patients. Focusing on apparently isolated 3q29 duplications, patients present mainly mild NDD as suggested by a high rate of learning disabilities in contrast to a low proportion of patients with intellectual disabilities. Although some are de novo, most of the 3q29 duplications are inherited from a parent with a similar mild phenotype. Besides, the study of small 3q29 duplications does not provide evidence for any critical region. Our data suggest that the overlapping and recurrent 3q29 duplications seem to lead to mild NDD and that a severe or syndromic clinical presentation should warrant further genetic analyses.

LRRK2 Kinase Inhibitor PF-06447475 Protects Drosophila melanogaster against Paraquat-Induced Locomotor Impairment, Life Span Reduction, and Oxidative Stress.

Parkinson's disease (PD) is a complex multifactorial progressive neurodegenerative disease characterized by locomotor alteration due to the specific deterioration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc). Mounting evidence shows that human LRRK2 (hLRRK2) kinase activity is involved in oxidative stress (OS)-induced neurodegeneration, suggesting LRRK2 inhibition as a potential therapeutic target. We report that the hLRRK2 inhibitor PF-06447475 (PF-475) prolonged lifespan, increased locomotor activity, maintained DAergic neuronal integrity, and reduced lipid peroxidation (LPO) in female Drosophila melanogaster flies chronically exposed to paraquat (PQ), a redox cycling compound, compared to flies treated with vehicle only. Since LRRK2 is an evolutionary conserved kinase, the present findings reinforce the idea that either reduction or inhibition of the LRRK2 kinase might decrease OS and locomotor alterations associated with PD. Our observations highlight the importance of uncovering the function of the hLRRK2 orthologue dLrrk2 in D. melanogaster as an excellent model for pharmacological screenings.

Combination of Tramiprosate, Curcumin, and SP600125 Reduces the Neuropathological Phenotype in Familial Alzheimer Disease PSEN1 I416T Cholinergic-like Neurons.

Familial Alzheimer's disease (FAD) is a complex and multifactorial neurodegenerative disorder for which no curative therapies are yet available. Indeed, no single medication or intervention has proven fully effective thus far. Therefore, the combination of multitarget agents has been appealing as a potential therapeutic approach against FAD. Here, we investigated the potential of combining tramiprosate (TM), curcumin (CU), and the JNK inhibitor SP600125 (SP) as a treatment for FAD. The study analyzed the individual and combined effects of these two natural agents and this pharmacological inhibitor on the accumulation of intracellular amyloid beta iAß; hyperphosphorylated protein TAU at Ser202/Thr205; mitochondrial membrane potential (ΔΨm); generation of reactive oxygen species (ROS); oxidized protein DJ-1; proapoptosis proteins p-c-JUN at Ser63/Ser73, TP53, and cleaved caspase 3 (CC3); and deficiency in acetylcholine (ACh)-induced transient Ca2+ influx response in cholinergic-like neurons (ChLNs) bearing the mutation I416T in presenilin 1 (PSEN1 I416T). We found that single doses of TM (50 µM), CU (10 µM), or SP (1 µM) were efficient at reducing some, but not all, pathological markers in PSEN 1 I416T ChLNs, whereas a combination of TM, CU, and SP at a high (50, 10, 1 µM) concentration was efficient in diminishing the iAß, p-TAU Ser202/Thr205, DJ-1Cys106-SO3, and CC3 markers by -50%, -75%, -86%, and -100%, respectively, in PSEN1 I417T ChLNs. Although combinations at middle (10, 2, 0.2) and low (5, 1, 0.1) concentrations significantly diminished p-TAU Ser202/Thr205, DJ-1Cys106-SO3, and CC3 by -69% and -38%, -100% and -62%, -100% and -62%, respectively, these combinations did not alter the iAß compared to untreated mutant ChLNs. Moreover, a combination of reagents at H concentration was able to restore the dysfunctional ACh-induced Ca2+ influx response in PSEN 1 I416T. Our data suggest that the use of multitarget agents in combination with anti-amyloid (TM, CU), antioxidant (e.g., CU), and antiapoptotic (TM, CU, SP) actions might be beneficial for reducing iAß-induced ChLN damage in FAD.

Sildenafil Reverses the Neuropathological Alzheimer's Disease Phenotype in Cholinergic-Like Neurons Carrying the Presenilin 1 E280A Mutation.

Background: Familial Alzheimer's disease (FAD) presenilin 1 E280A (PSEN 1 E280A) is characterized by functional impairment and the death of cholinergic neurons as a consequence of amyloid-ß (Aß) accumulation and abnormal phosphorylation of the tau protein. Currently, there are no available therapies that can cure FAD. Therefore, new therapies are urgently needed for treating this disease. Objective: To assess the effect of sildenafil (SIL) on cholinergic-like neurons (ChLNs) harboring the PSEN 1 E280A mutation. Methods: Wild-type (WT) and PSEN 1 E280A ChLNs were cultured in the presence of SIL (25µM) for 24 h. Afterward, proteinopathy, cell signaling, and apoptosis markers were evaluated via flow cytometry and fluorescence microscopy. Results: We found that SIL was innocuous toward WT PSEN 1 ChLNs but reduced the accumulation of intracellular Aß fragments by 87%, decreased the non-physiological phosphorylation of the protein tau at residue Ser202/Thr205 by 35%, reduced the phosphorylation of the proapoptotic transcription factor c-JUN at residue Ser63/Ser73 by 63%, decreased oxidized DJ-1 at Cys106-SO3 by 32%, and downregulated transcription factor TP53 (tumor protein p53), BH-3-only protein PUMA (p53 upregulated modulator of apoptosis), and cleaved caspase 3 (CC3) expression by 20%, 32%, and 22%, respectively, compared with untreated mutant ChLNs. Interestingly, SIL also ameliorated the dysregulation of acetylcholine-induced calcium ion (Ca2+) influx in PSEN 1 E280A ChLNs. Conclusions: Although SIL showed no antioxidant capacity in the oxygen radical absorbance capacity and ferric ion reducing antioxidant power assays, it might function as an anti-amyloid and antiapoptotic agent and functional neuronal enhancer in PSEN 1 E280A ChLNs. Therefore, the SIL has therapeutic potential for treating FAD.

Rotenone Induces a Neuropathological Phenotype in Cholinergic-like Neurons Resembling Parkinson's Disease Dementia (PDD).

Parkinson's disease with dementia (PDD) is a neurological disorder that clinically and neuropathologically overlaps with Parkinson's disease (PD) and Alzheimer's disease (AD). Although it is assumed that alpha-synuclein ( α -Syn), amyloid beta (A ß ), and the protein Tau might synergistically induce cholinergic neuronal degeneration, presently the pathological mechanism of PDD remains unclear. Therefore, it is essential to delve into the cellular and molecular aspects of this neurological entity to identify potential targets for prevention and treatment strategies. Cholinergic-like neurons (ChLNs) were exposed to rotenone (ROT, 10 µ M) for 24 h. ROT provokes loss of Δ Ψ m , generation of reactive oxygen species (ROS), phosphorylation of leucine-rich repeated kinase 2 (LRRK2 at Ser935) concomitantly with phosphorylation of α -synuclein ( α -Syn, Ser129), induces accumulation of intracellular A ß (iA ß ), oxidized DJ-1 (Cys106), as well as phosphorylation of TAU (Ser202/Thr205), increases the phosphorylation of c-JUN (Ser63/Ser73), and increases expression of proapoptotic proteins TP53, PUMA, and cleaved caspase 3 (CC3) in ChLNs. These neuropathological features resemble those reproduced in presenilin 1 (PSEN1) E280A ChLNs. Interestingly, anti-oxidant and anti-amyloid cannabidiol (CBD), JNK inhibitor SP600125 (SP), TP53 inhibitor pifithrin- α (PFT), and LRRK2 kinase inhibitor PF-06447475 (PF475) significantly diminish ROT-induced oxidative stress (OS), proteinaceous, and cell death markers in ChLNs compared to naïve ChLNs. In conclusion, ROT induces p- α -Syn, iA ß , p-Tau, and cell death in ChLNs, recapitulating the neuropathology findings in PDD. Our report provides an excellent in vitro model to test for potential therapeutic strategies against PDD. Our data suggest that ROT induces a neuropathologic phenotype in ChLNs similar to that caused by the mutation PSEN1 E280A.

Next generation phenotyping for diagnosis and phenotype-genotype correlations in Kabuki syndrome.

The field of dysmorphology has been changed by the use Artificial Intelligence (AI) and the development of Next Generation Phenotyping (NGP). The aim of this study was to propose a new NGP model for predicting KS (Kabuki Syndrome) on 2D facial photographs and distinguish KS1 (KS type 1, KMT2D-related) from KS2 (KS type 2, KDM6A-related). We included retrospectively and prospectively, from 1998 to 2023, all frontal and lateral pictures of patients with a molecular confirmation of KS. After automatic preprocessing, we extracted geometric and textural features. After incorporation of age, gender, and ethnicity, we used XGboost (eXtreme Gradient Boosting), a supervised machine learning classifier. The model was tested on an independent validation set. Finally, we compared the performances of our model with DeepGestalt (Face2Gene). The study included 1448 frontal and lateral facial photographs from 6 centers, corresponding to 634 patients (527 controls, 107 KS); 82 (78%) of KS patients had a variation in the KMT2D gene (KS1) and 23 (22%) in the KDM6A gene (KS2). We were able to distinguish KS from controls in the independent validation group with an accuracy of 95.8% (78.9-99.9%, p < 0.001) and distinguish KS1 from KS2 with an empirical Area Under the Curve (AUC) of 0.805 (0.729-0.880, p < 0.001). We report an automatic detection model for KS with high performances (AUC 0.993 and accuracy 95.8%). We were able to distinguish patients with KS1 from KS2, with an AUC of 0.805. These results outperform the current commercial AI-based solutions and expert clinicians.

Clinical, Neuroimaging, and Metabolic Footprint of the Neurodevelopmental Disorder Caused by Monoallelic HK1 Variants.

Background and Objectives: Hexokinase 1 (encoded by HK1) catalyzes the first step of glycolysis, the adenosine triphosphate-dependent phosphorylation of glucose to glucose-6-phosphate. Monoallelic HK1 variants causing a neurodevelopmental disorder (NDD) have been reported in 12 individuals. Methods: We investigated clinical phenotypes, brain MRIs, and the CSF of 15 previously unpublished individuals with monoallelic HK1 variants and an NDD phenotype. Results: All individuals had recurrent variants likely causing gain-of-function, representing mutational hot spots. Eight individuals (c.1370C>T) had a developmental and epileptic encephalopathy with infantile onset and virtually no development. Of the other 7 individuals (n = 6: c.1334C>T; n = 1: c.1240G>A), 3 adults showed a biphasic course of disease with a mild static encephalopathy since early childhood and an unanticipated progressive deterioration with, e.g., movement disorder, psychiatric disease, and stroke-like episodes, epilepsy, starting in adulthood. Individuals who clinically presented in the first months of life had (near)-normal initial neuroimaging and severe cerebral atrophy during follow-up. In older children and adults, we noted progressive involvement of basal ganglia including Leigh-like MRI patterns and cerebellar atrophy, with remarkable intraindividual variability. The CSF glucose and the CSF/blood glucose ratio were below the 5th percentile of normal in almost all CSF samples, while blood glucose was unremarkable. This biomarker profile resembles glucose transporter type 1 deficiency syndrome; however, in HK1-related NDD, CSF lactate was significantly increased in all patients resulting in a substantially different biomarker profile. Discussion: Genotype-phenotype correlations appear to exist for HK1 variants and can aid in counseling. A CSF biomarker profile with low glucose, low CSF/blood glucose, and high CSF lactate may point toward monoallelic HK1 variants causing an NDD. This can help in variant interpretation and may aid in understanding the pathomechanism. We hypothesize that progressive intoxication and/or ongoing energy deficiency lead to the clinical phenotypes and progressive neuroimaging findings.

APOE3 Christchurch modulates ß-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer's cases.

A patient with the PSEN1 E280A mutation and homozygous for APOE3 Christchurch (APOE3Ch) displayed extreme resistance to Alzheimer's disease (AD) cognitive decline and tauopathy, despite having a high amyloid burden. To further investigate the differences in biological processes attributed to APOE3Ch, we generated induced pluripotent stem (iPS) cell-derived cerebral organoids from this resistant case and a non-protected control, using CRISPR/Cas9 gene editing to modulate APOE3Ch expression. In the APOE3Ch cerebral organoids, we observed a protective pattern from early tau phosphorylation. ScRNA sequencing revealed regulation of Cadherin and Wnt signaling pathways by APOE3Ch, with immunostaining indicating elevated ß-catenin protein levels. Further in vitro reporter assays unexpectedly demonstrated that ApoE3Ch functions as a Wnt3a signaling enhancer. This work uncovered a neomorphic molecular mechanism of protection of ApoE3 Christchurch, which may serve as the foundation for the future development of protected case-inspired therapeutics targeting AD and tauopathies.

Glucose promotes resistance in lymphocytes against oxidative stress-induced apoptosis through signaling and metabolic pathways. Implications for Parkinson's disease / La glucosa promueve la resistencia en linfocitos contra el estrés oxidativo que induce apoptosis a través de rutas de señalización y metabólica. Impacto en la enfermedad de Parkinson / A glucose promove a resistência em linfócitos contra o estresse oxidativo que induz apoptose a través de rotas de sinalização e metabólica. Impacto na doença de Parkinson

SUMMARY Introduction: Parkinson's disease (PD) is a neurological disorder associated with the selective loss of dopaminergic (DAergic) neurons. Clinical data suggest that oxidative stress (OS) and dysregulation of glucose (G) metabolism are early events in PD. However, no data are available to explain the molecular connection between glucose metabolism, OS, and neuronal demise in PD. Human lymphocytes share a similar dopaminergic signaling mechanism with DAergic neurons. Further, rotenone (ROT) is a mitochondrial complex I inhibitor that selectively induces apoptosis through OS in dopaminergic neurons and lymphocytes. Thus, to test the hypothesis that G metabolism and OS are linked in dopaminergic system toxicity and PD, human lymphocytes were cultured with ROT in the presence or absence of various concentrations of glucose. Objective: This study examines the response of human lymphocytes to glucose (11, 55, 166, 277, 555 mM G) in the absence or presence of ROT (250 microM). Methods: Light and fluorescence microscopy and immunocytochemistry techniques were used to evaluate morphological and biochemical changes in human lymphocytes. Results: 55 mM G was effective in suppressing ROT-induced apoptosis in lymphocytes via 5 pathways: (i) pentose phosphate pathway (PPP), (ii) glutathione (GSH) pathway, (iii) superoxide dismutase (SOD) and catalase (CAT) antioxidant systems, and (iv) Phosphoinositide 3-kinase (PI3-K) signaling. Additionally, we report for the first time that G rescued lymphocytes from ROT-induced apoptosis by (v) activating NF-kB and down-regulating p53 and caspase-3. Signaling (e.g., LY294002) and metabolic inhibitors of these pathways (e.g., dehydroepiandrosterone (DHEA), L-buthioninesulfoximine (BSO), 1,3-Bis (2-chloroethyl)-1-nitrosourea (BCNU), mercaptosuccinic acid (MS), 3-amino-1,2,4- triazole (AT), sodium diethyldithiocarbamate (DDC)) only partially reversed the protective effect of 55 mM G on lymphocytes exposed to ROT. Conclusion: These data suggest that high G simultaneously triggers cellular signaling and antioxidant systems to ensure global cell protection against stressful conditions in DAergic.

RESUMEN Introducción: la enfermedad de Parkinson (EP) es un trastorno neurológico asociado con la pérdida selectiva de neuronas dopaminérgicas (DAérgicas). Datos clínicos sugieren que el estrés oxidativo (EO) y la desregulación del metabolismo de la glucosa (G) son eventos tempranos en la EP. Sin embargo, no existe información que explique la posible asociación molecular entre el metabolismo de la glucosa, el EO y la muerte neuronal. Los linfocitos humanos comparten mecanismos de señalización DAérgicos comunes. Más aún, la rotenona (ROT) es un inhibidor que selectivamente induce apoptosis vía EO en neuronas DAérgicas y linfocitos. Para evaluar la hipótesis que el metabolismo de la G y el EO están asociados con la toxicidad del sistema DAérgicas y EP, se cultivaron linfocitos humanos con ROT en presencia o ausencia de varias concentraciones de G. Objetivo: este estudio examina la respuesta de los linfocitos a G (11, 55, 166, 277, 555 mM) en ausencia o presencia de ROT (250 microM). Métodos: se utilizaron técnicas de microscopía de luz y fluorescencia e inmunocitoquímica para evaluar los cambios morfológicos y bioquímicos de los linfocitos. Resultados: la G 55 mM fue eficaz en suprimir la apoptosis en linfocitos inducida por ROT vía activación de 5 rutas metabólicas: (i) la vía pentosa fosfato, (ii) la vía glutatión; (iii) los sistemas antioxidantes superóxido dismutasa (SOD) y catalasa (CAT); (iv) fosfoinositol 3 cinasa (PI3-K). Además, se observó por primera vez que la G rescata linfocitos de la apoptosis inducida por ROT vía (v) activación del factor nuclear kappa-B (NFkB) y por regulación a la baja de p53 y de la caspasa-3. Se demostró que los inhibidores de señalización (v.gr. LY294002) e inhibidores metabólicos (v.gr. DHEA, BSO, BCNU, MS, DCC) revierten parcialmente los efectos citoprotectores de la G 55 mM en linfocitos expuestos a ROT. Conclusión: estos hallazgos sugieren que la alta concentración de G induce simultáneamente sistemas de señalización y antioxidantes para asegurar la protección global de la célula contra condiciones estresantes en células DAérgicas.

RESUMO Introdução: a doença de Parkinson (PD) é uma desordem neurológica associada a perda seletiva de neurônios dopaminérgicos (Daergicas). Dados clínicos sugerem que o estresse oxidativo (EO) e a desregulação do metabolismo da glicose (G) são eventos iniciais no PD. No entanto, não há nenhuma informação que explica a possível associação molecular entre o metabolismo da glicose, EO e morte neuronal. Linfócitos humanos compartilham comum Daergicos mecanismos de sinalização. Além disso, a rotenona (ROT) é um inibidor que seletivamente induz apoptose através de EO nos neurônios Daergicas e linfócitos. Para avaliar a hipótese de que o metabolismo do G e EO estão associadas com a toxicidade do Daergicas e sistema de EP, linfócitos humanos com ROT foram cultivados na presença ou ausência de várias concentrações de G. Objetivo: este estudo analisa a resposta dos linfócitos a G (55 11, 166, 277, 555 mM) na ausência ou presença de podridão (250 microM). Métodos: luz e imunocitoquímica, microscopia de fluorescência foram utilizadas técnicas para avaliar as alterações morfológicas e bioquímicas de linfócitos. Resultados: a 55mM G foi eficaz em suprimir a apoptose em linfócitos induzidos por (ROT) a través da ativação de 5 vias metabólicas: (i) a través do fosfato de pentose, (ii) a través de glutationa; (iii) a superóxido dismutase de antioxidante (SOD) e catalase (CAT) sistemas; (iv) Phosphoinositide 3 cinase (PI3-K). Além disso, foi observada pela primeira vez que o G resgata a apoptose de linfócitos induzida por (ROT) via ativação (v) por fator nuclear kappa-B, (NF-kB) e por regulação por baixo de p53 e Caspase-3. Mostrou que inibidores (por exemplo, LY294002), inibidores de sinalização e metabólicos (por exemplo, DHEA, BSO, BCNU, MS, DCC) reverteu parcialmente os efeitos dos tilacoides do G 55 mM de linfócitos expostos à (ROT). Conclusão: estes resultados sugerem que a alta concentração de G induz simultaneamente antioxidantes e sistemas de sinalização para garantir a proteção global da célula de condições estressantes nas células Daergicas.

Los linfocitos: modelo de estudio en las enfermedades de Alzheimer y Parkinson / Linfocitos as a cell model to study Alzheimer´s and Parkison´s diseases

Las enfermedades de Alzheimer familiar (EAF) y de Parkinson familiar (EPF) son dos entidades neurodegenerativas progresivas que afectan a un grupo numeroso de individuos en el departamento de Antioquia, Colombia. Hasta el presente no existe un tratamiento eficaz y definitivo que reduzca, o detenga, el deterioro clinicopatológico que padecen los pacientes de estas devastadoras enfermedades neurodegenerativas. Por estas razones, los procesos bioquímicos comprometidos en la pérdida neuronal han sido esencialmente estudiados en modelos biológicos. Los autores de este artículo, basados en su propia experiencia y en la de otros investigadores, postulan a los linfocitos como modelo celular de estudio para dilucidar las señales moleculares intracelulares activadas por el en las enfermedades de Alzheimer y Parkinson. Sorprendentemente, los linfocitos poseen una similitud celular y bioquímica con las células nerviosas. De hecho, los linfocitos expresan por lo menos 6 sistemas biológicos, considerados como pertenecientes únicamente a las neuronas, tales como los sistemas catecolaminérgico, serotonérgico, acetilcolinérgico, glutamaérgico, noradrenérgico, gabaérgico. Debido a que los linfocitos son células con ciclo celular en la etapa Go, y presentan los sistemas metabólicos de síntesis, transporte y procesamiento de las proteínas precursora del beta-amiloide (APP), presenilinas y parkina, estas células constituyen un modelo celular ideal que permitirá una mejor comprensión de la señalización patológica de los procesos neurodegenerativos, y además permitirá realizar un enfoque racional de los diseños terapéuticos que detengan las causas de deterioro neuronal en los pacientes que padecen estas enfermedades.

Alzheimer's disease (AD) and parkinson's disease (PD) are two common progressive neurodegenerative disorders that affect a large group of individuals in Antioquia, Colombia. Up till now, there is not an effective and definitive therapeutic treatment aimed to reduce or retard the clinic and pathologic symptoms induced by both devastating diseases. Thus, the biochemical mechanism(s) involved in neural loss has mainly been studied in biological models. In this article the authors, based on their own scientific experience and others, have proposed lymphocytes as a cellular model to study the molecular signalling mechanism induced by oxidative stress in AD and PD. Remarkably, lymphocytes and neurons are cellularly and biochemically alike. Indeed, lymphocytes express at least six different biological systems such as catecholaminergic, serotonergic, acetylcholinergic, glutamatergic, noradrenergic and GABAergic systems considered to be exclusively pertain to neural cells!. Given that lymphocytes are post-mitotic cells (i.e. Go cell cycle) and possess the synthesis, transport and processing systems of amyloid-beta precursor protein (AßPP), presenilins and parkin proteins, these cells constitute not only an ideal bio-model to better understanding of the pathological signalling in those neurodegenerative processes, but also represent a meaningful tool to design innovative and rational therapeutic strategies focussed to arrest the neuronal death in Alzheimer's and Parkinson's patients from Antioquia.

Modelo molecular unificado de estrés oxidativo en las enfermedades de Alzheimer y Parkinson / Unified molecular model of stress oxidative in diseases Alzheimer's and Parkinson's

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most frequent progressive neurodegenerative diseases affecting millions of people in the world. Because a significant percentage of patients share common clinical and pathological features from both entities, this may indicate the existence of a common pathological mechanism. Based on in vitro and in situ data, authors proposed an unified molecular oxidative stress model induced by dopamine (DA), 6-hydroxydopamine (6-OHDA); 5,6 & 5,7-dihydrytryptamine (5,6 & 5,7 DHT); amyloid beta 25-35 (Aß25-35), and metals [e. g. iron (Fe2+), copper (Cu2+), zinc (Zn2+), manganese (Mn2+)], as a possible explanation of neural loss in AD/PD overlapping cases. This hypothesis might contribute to a better understanding of the pathophysiology cascades of both disorders, and also support the notion that oxidative stress generated by H2O2 represent an essential molecule of intracellular signalization leading to cell death. Taken together, these findings might allow a better rational approach to therapeutic design that rescue, delay or retard cell death in patients suffering from those deteriorating disorders.

La enfermedad de Alzheimer (EA) y la enfermedad de Parkinson (EP) son los trastornos neurodegenerativos progresivos que afectan con mayor frecuencia a millones de personas en el mundo. Dado que un porcentaje significativo de pacientes comparten características clínicas y patológicas de ambas entidades, esto podría indicar la existencia de un mecanismo patológico común. Con base en estudios in vitro e in situ, los autores proponen un modelo molecular unificado de estrés oxidativo en EA y EP, inducido por los estímulos tóxicos, la dopamina (DA), la 6- hidroxidopamina (6-OHDA), la 5,6-dihidroxitriptamina (5,6-DHT), la 5,7-dihidroxitriptamina (5,7-DHT), el beta-amiloide 25-35 (Aß[25-35]) y los metales (v. gr. hierro [Fe2+], cobre [Cu2+], cinc [Zn2+], manganeso [Mn2+]) como posible explicación a la pérdida neuronal en algunos casos mixtos con EA/EP. Esta hipótesis podría contribuir a una mejor comprensión de las cascadas fisiopatológicas en ambos desórdenes y valida la idea de que el estrés oxidativo generado por el peróxido de hidrógeno (H2 O2) representa una molécula fundamental de señalización de muerte celular. En conjunto, estas investigaciones permitirían un mejor acercamiento racional en los diseños terapéuticos que rescaten, detengan o retarden los procesos de deterioro neuronal en los pacientes que padecen estas devastadoras patologías.

Seguridad e inmunogenicidad de una vacuna de polisacárido Vi de salmonella typhi en jóvenes cubanos / Security and immunogenecity of a vaccine of polyssacharide Vi from salmonella typhi in cuban youths

Se realizó un estudio aleatorizado, controlado y a doble ciegas, en adultos jóvenes de 18 a 20 años, con el objetivo de evaluar la reactogenicidad y la inmunogenicidad de vax-TyViâ, vacuna de polisacárido Vi de Salmonella typhi. Se distribuyeron en 3 grupos; inmunizados con una dosis de vax-TyViâ (Instituto Finlay), TYPHIM ViTM (Pasteur-Mérieux) o vax-TETâ (toxoide tetánico). Se tomaron muestras de suero antes y 21 d después de la inmunización. La inmunogenicidad se evaluó en 323 voluntarios mediante un ELISA indirecto. La seroconversión de los que recibieron vax-TyViâ fue 81,97 por ciento y de 65,05 por ciento para TYPHIM ViTM. Los títulos medios geométricos posvacunales fueron 7,41 U/mL (5,92û9,27 U/mL) y 5,41 U/mL (4,35û6,72 U/mL) respectivamente. La seroconversión con vax-TETâ fue 0 por ciento. La reactogenicidad de ambas vacunas polisacarídicas fue baja. Se concluyó que la inmunogenicidad de vax-TyViâ no fue inferior a la de TYPHIM ViTM y su reactogenicidad resultó similar

La apoptosis en las enfermedades neurodegenerativas / Apoptosis in neurodegenerative disorders: consensus and controversies

Las enfermedades de Alzheimer, de Parkinson de Huntington y de Wilson son un grupo de trastornos neurológicos heterogéneos que se caracterizan por una pérdida selectiva y simétrica de las neuronas motoras, sensoriales o de los sistemas cognitivos con manifestación crónica y progresiva. Durante los últimos años, se postulaba la apoptosis como el tipo de muerte neuronal responsable en el proceso de neurodegeneración. Basados en información reciente, los autores analizan críticamente las evidencias morfológicas y/o bioquímicas de muerte por apoptosis en tejido cerebral post mortem. Aunque se han publicado innumerables trabajos al respecto, hasta el presente no existe un consenso generalizado que implique formalmente la apoptosis como el mecanismo de muerte neuronal. De hecho, las evidencias morfológicas y bioquímicas son insuficientes y contradictorias. Además, la contribución de las proteínas mutadas o alteradas metabólicamente en la patogénesis de estos desórdenes, está aún por ser establecida. El reto científico actual es caracterizar y elucidar las interacciones de dichas proteínas mutadas en las neuronas afectadas y determinar la cascada de eventos metabólicos que conducen a la neurona a su muerte. El esclarecimiento de estos mecanismos moleculares podría proporcionar información esencial para el diseño de tratamientos que inhiban o prevengan el desarrollo de las enfermedades neurodegenerativas en los individuos afectados