Iron, Ferritin, Hereditary Ferritinopathy, and Neurodegeneration

Cellular growth, function, and protection require proper iron management, and ferritin plays a crucial role as the major iron sequestration and storage protein. Ferritin is a 24 subunit spherical shell protein composed of both light (FTL) and heavy chain (FTH1) subunits, possessing complimentary iron-handling functions and forming three-fold and four-fold pores. Iron uptake through the three-fold pores is well-defined, but the unloading process somewhat less and generally focuses on lysosomal ferritin degradation although it may have an additional, energetically efficient pore mechanism. Hereditary Ferritinopathy (HF) or neuroferritinopathy is an autosomal dominant neurodegenerative disease caused by mutations in the FTL C-terminal sequence, which in turn cause disorder and unraveling at the four-fold pores allowing iron leakage and enhanced formation of toxic, improperly coordinated iron (ICI). Histopathologically, HF is characterized by iron deposition and formation of ferritin inclusion bodies (IBs) as the cells overexpress ferritin in an attempt to address iron accumulation while lacking the ability to clear ferritin and its aggregates. Overexpression and IB formation tax cells materially and energetically, i.e., their synthesis and disposal systems, and may hinder cellular transport and other spatially dependent functions. ICI causes cellular damage to proteins and lipids through reactive oxygen species (ROS) formation because of high levels of brain oxygen, reductants and metabolism, taxing cellular repair. Iron can cause protein aggregation both indirectly by ROS-induced protein modification and destabilization, and directly as with mutant ferritin through C-terminal bridging. Iron release and ferritin degradation are also linked to cellular misfunction through ferritinophagy, which can release sufficient iron to initiate the unique programmed cell death process ferroptosis causing ROS formation and lipid peroxidation. But IB buildup suggests suppressed ferritinophagy, with elevated iron from four-fold pore leakage together with ROS damage and stress leading to a long-term ferroptotic-like state in HF. Several of these processes have parallels in cell line and mouse models. This review addresses the roles of ferritin structure and function within the above-mentioned framework, as they relate to HF and associated disorders characterized by abnormal iron accumulation, protein aggregation, oxidative damage, and the resulting contributions to cumulative cellular stress and death

Iluminación de obras de arte

La iluminación de bienes y patrimonios culturales plantea una situación de compromiso entre las necesidades de exhibición y las de conservación. El sistema de alumbrado debe conjugar cualidades perceptivas (visión de detalle, correcta apreciación del color, destaque de la obra) y un mínimo nivel de daño. En el presente trabajo se detalla el estudio de la iluminación artificial a la que se encuentra sometido un ícono bizantino, “Virgen de la Rosa” originario de Constantinopla y datado en el siglo XV, que se expone en la Iglesia de San Francisco (calle 12 entre 68 y 69 - La Plata). El sistema de iluminación actual está formado por una combinación de lámparas incandescentes reflectoras y lámparas fluorescentes. Tomando como referencia las recomendaciones de la Comisión Internacional de Alumbrado CIE, se realizaron mediciones de niveles de iluminancia, luminancia y color en el área de exposición. Se detectaron niveles de iluminancias mayores a los permitidos, junto con presencia de radiación UV potencialmente dañina para los barnices de la obra. El trabajo concluye con recomendaciones para un nuevo sistema de iluminación basado en fuentes LEDs, que disminuirían notablemente el nivel de agresión, mejorando las características estéticas del conjunto.Tópico 2: Conservación y restauración de pinturas, cueros, textiles, papel y metales. Técnicas de limpieza y restauración

ENSEÑANZA MODULAR EN EL DESARROLLO DE LA COMPETENCIA RESOLUCIÓN DE PROBLEMAS DE GENÉTICA MENDELIANA DE LOS ESTUDIANTES DE INGENIERÍA AGRONÓMICA DE LA UNHEVAL, 2018

La educación superior universitaria caracterizada porque la responsabilidad formativa corresponde a profesionales de la carrera, quienes no siempre utilizan adecuados recursos didácticos, determina carencias en los estudiantes. Ante la dificultad de los estudiantes para resolver problemas de genética, se realizó la investigación planteando la pregunta: ¿qué efectos produce la enseñanza modular en el desarrollo de la competencia de resolución de problemas de genética mendeliana, en los estudiantes de Ingeniería Agronómica de la UNHEVAL, 2018?. La investigación de tipo aplicada, enfoque cuantitativo, nivel explicativo y diseño cuasi experimental, se desarrolló en una población de 62 estudiantes del segundo año de Ingeniería Agronómica que cursaron la asignatura de Genética. Se tomó dos muestras relacionadas no probabilísticas, de tipo intencionado, conformadas por los grupos experimental y control cada uno con 23 estudiantes, recibieron enseñanza modular y expositiva, respectivamente. La evaluación a ambos grupos consideró seis indicadores para la dimensión cognitiva y procedimental; cuatro para la actitudinal. Los datos de indicadores cognitivos se analizaron mediante la prueba de Student; los procedimentales y actitudinales, con la prueba no paramétrica de Wilcoxon; ambos a una probabilidad del 0.05. Se estableció diferencia estadística para la dimensión cognitiva entre el grupo experimental con promedio de 14.04 y 13.0 % ubicados en el nivel excelente, superó al grupo control con promedio de 5.17 y 56.5 % con nivel deficiente. En la dimensión procedimental, el 39.85 % del grupo experimental logró nivel competente, frente al 3.61 % del grupo control. Para la dimensión actitudinal, no se determinó diferencias entre ambos grupos, alcanzando nivel competente el 22.83 % del grupo experimental y 18.47 % del grupo control. El 47.83 % de estudiantes que recibieron enseñanza modular estuvieron totalmente de acuerdo con el método desarrollado. Se concluyó que la enseñanza modular mejora significativamente la competencia de resolución de problemas de genética mendeliana.Tesi

Colour appearance in led lighting

The paper shows a comparative study of colour comparison between white LED lamps and conventional ones (incandescent and compact fluorescent). The LED lamps used were a model designed by the direct replaces of halogen incandescent lamps. The technology used for white light generation was based on short waves emitter chips and secondary emission. As result of the experience, significant object colour coordinates displacements in LEDs lighting were observed. As it was predictable from LEDs spectral distribution, orange – red colours were poorly reproduced. However, the subjective experience did not show a remarkable preference to the conventional light sources. Furthermore, several observers qualified the objects under LEDs light as “more naturals”

Amyloid and intracellular accumulation of BRI2

Familial British dementia (FBD) and familial Danish dementia (FDD) are caused by mutations in the BRI2 gene. These diseases are characterized clinically by progressive dementia and ataxia and neuropathologically by amyloid deposits and neurofibrillary tangles. Herein, we investigate BRI2 protein accumulation in FBD, FDD, Alzheimer disease and Gerstmann-Sträussler-Scheinker disease. In FBD and FDD, we observed reduced processing of the mutant BRI2 pro-protein, which was found accumulating intracellularly in the Golgi of neurons and glial cells. In addition, we observed an accumulation of a mature form of BRI2 protein in dystrophic neurites, surrounding amyloid cores. Accumulation of BRI2 was also observed in dystrophic neurites of Alzheimer disease and Gerstmann-Sträussler-Scheinker disease cases. Although it remains to be determined whether intracellular accumulation of BRI2 may lead to cell damage in these degenerative diseases, our study provides new insights into the role of mutant BRI2 in the pathogenesis of FBD and FDD and implicates BRI2 as a potential indicator of neuritic damage in diseases characterized by cerebral amyloid deposition

Abnormal iron metabolism in fibroblasts from a patient with the neurodegenerative disease hereditary ferritinopathy

<p>Abstract</p> <p>Background</p> <p>Nucleotide duplications in exon 4 of the ferritin light polypeptide (FTL) gene cause the autosomal dominant neurodegenerative disease neuroferritinopathy or hereditary ferritinopathy (HF). Pathologic examination of patients with HF has shown abnormal ferritin and iron accumulation in neurons and glia in the central nervous system (CNS) as well as in cells of other organ systems, including skin fibroblasts. To gain some understanding on the molecular basis of HF, we characterized iron metabolism in primary cultures of human skin fibroblasts from an individual with the <it>FTL c.497_498dupTC </it>mutation.</p> <p>Results</p> <p>Compared to normal controls, HF fibroblasts showed abnormal iron metabolism consisting of increased levels of ferritin polypeptides, divalent metal transporter 1, basal iron content and reactive oxygen species, and decreased levels of transferrin receptor-1 and IRE-IRP binding activity.</p> <p>Conclusions</p> <p>Our data indicates that HF fibroblasts replicate the abnormal iron metabolism observed in the CNS of patients with HF. We propose that HF fibroblasts are a unique cellular model in which to study the role of abnormal iron metabolism in the pathogenesis of HF without artifacts derived from over-expression or lack of endogenous translational regulatory elements.</p

Evidence for Lymphatic Aβ Clearance in Alzheimer’s Transgenic Mice

Evidence has shown that lymphatic drainage contributes to removal of debris from the brain but its role in the accumulation of amyloid β peptides (Aβ) has not been demonstrated. We examined the levels of various forms of Aβ in the brain, plasma and lymph nodes in a transgenic model of Alzheimer’s disease (AD) at different ages. Herein, we report on the novel finding that Aβ is present in the cervical and axillary lymph nodes of AD transgenic mice and that Aβ levels in lymph nodes increase over time, mirroring the increase of Aβ levels observed in the brain. Aβ levels in lymph nodes were significantly higher than in plasma. At age 15.5 months, there was a significant increase of monomeric soluble Aβ40 (p=0.003) and Aβ42 (p=0.05) in the lymph nodes over the baseline values measured at 6 months of age. In contrast, plasma levels of Aβ40 showed no significant changes (p=0.68) and plasma levels Aβ42 significantly dropped (p=0.02) at the same age. Aβ concentration was low to undetectable in splenic lymphoid tissue and several other control tissues including heart, lung, liver, kidneys and intestine of the same animals, strongly suggesting that Aβ peptides in lymph nodes are derived from the brain

Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that is associated with repetitive head impacts or exposure to blast waves. First described as punch-drunk syndrome and dementia pugilistica in retired boxers1-3, CTE has since been identified in former participants of other contact sports, ex-military personnel and after physical abuse4-7. No disease-modifying therapies currently exist, and diagnosis requires an autopsy. CTE is defined by an abundance of hyperphosphorylated tau protein in neurons, astrocytes and cell processes around blood vessels8,9. This, together with the accumulation of tau inclusions in cortical layers II and III, distinguishes CTE from Alzheimer's disease and other tauopathies10,11. However, the morphologies of tau filaments in CTE and the mechanisms by which brain trauma can lead to their formation are unknown. Here we determine the structures of tau filaments from the brains of three individuals with CTE at resolutions down to 2.3 Å, using cryo-electron microscopy. We show that filament structures are identical in the three cases but are distinct from those of Alzheimer's and Pick's diseases, and from those formed in vitro12-15. Similar to Alzheimer's disease12,14,16-18, all six brain tau isoforms assemble into filaments in CTE, and residues K274-R379 of three-repeat tau and S305-R379 of four-repeat tau form the ordered core of two identical C-shaped protofilaments. However, a different conformation of the β-helix region creates a hydrophobic cavity that is absent in tau filaments from the brains of patients with Alzheimer's disease. This cavity encloses an additional density that is not connected to tau, which suggests that the incorporation of cofactors may have a role in tau aggregation in CTE. Moreover, filaments in CTE have distinct protofilament interfaces to those of Alzheimer's disease. Our structures provide a unifying neuropathological criterion for CTE, and support the hypothesis that the formation and propagation of distinct conformers of assembled tau underlie different neurodegenerative diseases

A novel ferritin light chain mutation in neuroferritinopathy with an atypical presentation

Neuroferritinopathy or hereditary ferritinopathy is an inherited neurodegenerative disease caused by mutations in ferritin light chain (FTL) gene. The clinical features of the disease are highly variable, and include a movement disorder, behavioral abnormalities, and cognitive impairment. Neuropathologically, the disease is characterized by abnormal iron and ferritin deposition in the central nervous system. We report a family in which neuroferritinopathy begins with chronic headaches, later developing progressive orolingual and arm dystonia, dysarthria, cerebellar ataxia, pyramidal tract signs, and psychiatric symptoms. In the absence of classic clinical symptoms, the initial diagnosis of the disease was based on magnetic resonance imaging studies. Biochemical studies on the proband showed normal serum ferritin levels, but remarkably low cerebrospinal fluid (CSF) ferritin levels. A novel FTL mutation was identified in the proband. Our findings expand the genetic and clinical diversity of neuroferritinopathy and suggest CSF ferritin levels as a novel potential biochemical marker for the diagnosis of neuroferritinopathy

Sub-3 Å Apoferritin Structure Determined With Full Range of Phase Shifts Using A Single Position Of Volta Phase Plate

Volta Phase Plate (VPP) has become an invaluable tool for cryo-EM structural determination of small protein complexes by increasing image contrast. Currently, the standard protocol of VPP usage periodically changes the VPP position to a fresh spot during data collection. Such a protocol was to target the phase shifts to a relatively narrow range (around 90°) based on the observations of increased phase shifts and image blur associated with more images taken with a single VPP position. Here, we report a 2.87 Å resolution structure of apoferritin reconstructed from a dataset collected using only a single position of VPP. The reconstruction resolution and map density features are nearly identical to the reconstruction from the control dataset collected with periodic change of VPP positions. Further experiments have verified that similar results, including a 2.5 Å resolution structure, could be obtained with a full range of phase shifts, different spots of variable phase shift increasing rates, and at different ages of the VPP post-installation. Furthermore, we have found that the phase shifts at low resolutions, probably related to the finite size of the Volta spots, could not be correctly modeled by current CTF model using a constant phase shift at all frequencies. In dataset III, severe beam tilt issue was identified but could be computationally corrected with iterative refinements. The observations in this study may provide new insights into further improvement of both the efficiency and robustness of VPP, and to help turn VPP into a plug-and-play device for high-resolution cryo-EM