Clearing extracellular alpha-synuclein from cerebrospinal fluid: A new therapeutic strategy in parkinson’s disease

This concept article aims to show the rationale of targeting extracellular α-Synuclein (α-Syn) from cerebrospinal fluid (CSF) as a new strategy to remove this protein from the brain in Parkinson’s disease (PD). Misfolding and intracellular aggregation of α-synuclein into Lewy bodies are thought to be crucial in the pathogenesis of PD. Recent research has shown that small amounts of monomeric and oligomeric α-synuclein are released from neuronal cells by exocytosis and that this extracellular alpha-synuclein contributes to neurodegeneration, progressive spreading of alpha-synuclein pathology, and neuroinflammation. In PD, extracellular oligomeric-α-synuclein moves in constant equilibrium between the interstitial fluid (ISF) and the CSF. Thus, we expect that continuous depletion of oligomeric-α-synuclein in the CSF will produce a steady clearance of the protein in the ISF, preventing transmission and deposition in the brain

¿Teorías sin teoría? Tras las huellas del primer pragmatismo en las perspectivas de Archer, Boltanski, Honneth y Latour

Frente a la generación de autores como Habermas, Luhmann, Giddens o Bourdieu, desde distintas miradas, Archer, Boltanski, Honneth y Latour han renovado los presupuestos y análisis de la teoría sociológica contemporánea. A pesar de una aparente disimilitud y distancia de sus propuestas, todas ellas han abrevado de forma fundamental en el “primer pragmatismo” norteamericano de Peirce, James y Dewey. Por tanto, con el objetivo de plasmar una mirada abarcativa multidimensional, este artículo rastrea las huellas del “primer pragmatismo” en las propuestas de Archer, Boltanski, Honneth y Latour, a partir de cinco dimensiones claves: la crítica a las dicotomías del pensamiento sociológico; el despliegue de una metodología como resolución de problemas prácticos; el estudio de la relaciones entre creencias, experiencias y efectos prácticos; la investigación de las modalidades a través de las cuales se forman grupos reales, que no pueden darse por sentado; y, por último, la intervención político-práctica entendida como ensanchamiento del mundo. Esto permite no solo señalar la centralidad actual del pragmatismo en la teoría sociológica, sino también dar cuenta de las múltiples dimensiones desde las cuales se lo puede abordar. Asimismo, tales análisis obligan a discutir en qué medida estas propuestas continúan o no el proyecto de elaborar teorías sociológicas

Increased neurotransmitter release at the neuromuscular junction in a mouse model of polyglutamine disease

In Huntington's disease (HD), the expansion of polyglutamine (polyQ) repeats at the N terminus of the ubiquitous protein huntingtin (htt) leads to neurodegeneration in specific brain areas. Neurons degenerating in HD develop synaptic dysfunctions. However, it is unknown whether mutant htt impacts synaptic function in general. To investigate that, we have focused on the nerve terminals of motor neurons that typically do not degenerate in HD. Here, we have studied synaptic transmission at the neuromuscular junction of transgenic mice expressing a mutant form of htt (R6/1 mice).Wehave found that the size and frequency of miniature endplate potentials are similar in R6/1 and control mice. In contrast, the amplitude of evoked endplate potentials in R6/1 mice is increased compared to controls. Consistent with a presynaptic increase of release probability, synaptic depression under high-frequency stimulation is higher in R6/1 mice. In addition, no changes were detected in the size and dynamics of the recycling synaptic vesicle pool. Moreover, we have found increased amounts of the synaptic vesicle proteins synaptobrevin 1,2/VAMP 1,2 and cysteine string protein-α, and the SNARE protein SNAP-25, concomitant with normal levels of other synaptic vesicle markers. Our results reveal that the transgenic expression of a mutant form of htt leads to an unexpected gain of synaptic function. That phenotype is likely not secondary to neurodegeneration and might be due to a primary deregulation in synaptic protein levels. Our findings could be relevant to understand synaptic toxic effects of proteins with abnormal polyQ repeats. Copyright©2011 the authors.Instituto de Salud Carlos III (Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas), the Spanish Ministry of Science and Innovation (BFU2007-66008 to R.F-C., SAF2009-08233 to J.J.L., and Juan de la Cierva contracts to J.L.R. and C.T.-Z.), Junta de Andalucía (P07-CVI- 02854, P06-CVI-02392), Comunidad Autónoma de Madrid, Fundación Ramón Areces, and Fondo Europeo de Desarrollo RegionalPeer Reviewe

Increased neurotransmitter release at the neuromuscular junction in a mouse model of polyglutamine disease

In Huntington’s disease (HD), the expansion of polyglutamine (polyQ) repeats at the N terminus of the ubiquitous protein huntingtin (htt) leads to neurodegeneration in specific brain areas. Neurons degenerating in HD develop synaptic dysfunctions. However, it is unknown whether mutant htt impacts synaptic function in general. To investigate that, we have focused on the nerve terminals of motor neurons that typically do not degenerate in HD. Here, we have studied synaptic transmission at the neuromuscular junction of transgenic mice expressing a mutant form of htt (R6/1 mice).Wehave found that the size and frequency of miniature endplate potentials are similar in R6/1 and control mice. In contrast, the amplitude of evoked endplate potentials in R6/1 mice is increased compared to controls. Consistent with a presynaptic increase of release probability, synaptic depression under high-frequency stimulation is higher in R6/1 mice. In addition, no changes were detected in the size and dynamics of the recycling synaptic vesicle pool. Moreover, we have found increased amounts of the synaptic vesicle proteins synaptobrevin 1,2/VAMP 1,2 and cysteine string protein-_, and the SNARE protein SNAP-25, concomitant with normal levels of other synaptic vesicle markers. Our results reveal that the transgenic expression of a mutant form of htt leads to an unexpected gain of synaptic function. That phenotype is likely not secondary to neurodegeneration and might be due to a primary deregulation in synaptic protein levels. Our findings could be relevant to understand synaptic toxic effects of proteins with abnormal polyQ repeats

Stigma, labeling, disrespect: Demeaning reclassifications in Goffman, Becker and Honneth

Este artículo propone una comparación teórica entre las perspectivas de Goffman, Becker y Honneth a partir del problema de las reclasificaciones sociales. Así, se focaliza en una preocupación compartida por estos autores: las reclasificaciones “degradantes”. Éstas implican modos de catalogar de manera negativa y lacerante a los individuos y grupos, con la imposición de “estigmas” (Goffman), el “etiquetamiento” de “desviados” (Becker) y el “menosprecio”, la “reificación” o la “ausencia o pérdida del reconocimiento” de individuos y grupos (Honneth). De esta manera, este trabajo da cuenta de sus propuestas destacando aquellas afinidades que comparten y que ubican a Goffman y a Becker como antecedentes ineludibles de la teoría de Honneth. Se sostiene que estas afinidades respecto de los procesos reclasificatorios y de las identidades degradantes se conectan tanto con su carácter experiencial, que involucra la afectividad y la corporalidad, como con la importancia de lo público, espacio decisivo para el despliegue de esos procesos e identidades. Además, se resalta cierto enfoque de Goffman y Becker a partir del cual es posible realizar un aporte enriquecedor a la propuesta de Honneth. Se trata de la constante negociación desplegada en los procesos reclasificatorios degradantes, en especial, en las relaciones entre el individuo y el “grupo degradado”, las cuales pueden implicar fuertes tensiones e, incluso, desgarramientos.This article proposes a theoretical comparison between the perspectives of Goffman, Becker and Honneth on the problem of social reclassifications. Thus, it focuses on a concern shared by these authors: “demeaning” reclassifications. These involve ways of negatively and laceratingly categorizing individuals and groups, with the imposition of "stigmas" (Goffman), the "labeling" of "deviants" (Becker) and the "disrespect", "reification" or "absence or loss of recognition" of individuals and groups (Honneth). In this way, this paper gives an account of their proposals highlighting those affinities that they share and that place Goffman and Becker as unavoidable antecedents of Honneth's theory. It is argued that these affinities regarding reclassifying processes and degrading identities are connected both with their experiential character, which involves affectivity and corporeality, and with the importance of the public, a decisive space for the deployment of these processes and identities. In addition, a certain approach of Goffman and Becker is highlighted, from which it is possible to make an enriching contribution to Honneth's proposal. This approach is related to the constant negotiation deployed in the degrading reclassifying processes, especially in the links between the individual and the "demeaned group", which may involve strong tensions and even tearing apart.Fil: Bialakowsky, Alejandro Marcos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; ArgentinaFil: Sasín, Mariano Gustavo. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; ArgentinaFil: Nougués, Tomás. Universidad del Salvador. Facultad de Ciencias Sociales; ArgentinaFil: Zapico, Manuel. Universidad del Salvador. Facultad de Ciencias Sociales; ArgentinaFil: Barrero, Julieta. Universidad del Salvador. Facultad de Ciencias Sociales; ArgentinaFil: Ichaso, Elisa. Universidad del Salvador. Facultad de Ciencias Sociales; ArgentinaFil: Bertelli, Agustin Alejandro. Universidad del Salvador. Facultad de Ciencias Sociales; Argentin

New, Fully Implantable Device for Selective Clearance of CSF-Target Molecules: Proof of Concept in a Murine Model of Alzheimer’s Disease

[EN] We have previously proposed a radical change in the current strategy to clear pathogenic proteins from the central nervous system (CNS) based on the cerebrospinal fluid (CSF)-sink therapeutic strategy, whereby pathogenic proteins can be removed directly from the CNS via CSF. To this aim, we designed and manufactured an implantable device for selective and continuous apheresis of CSF enabling, in combination with anti-amyloid-beta (Aβ) monoclonal antibodies (mAb), the clearance of Aβ from the CSF. Here, we provide the first proof of concept in the APP/PS1 mouse model of Alzheimer’s disease (AD). Devices were implanted in twenty-four mice (seventeen APP/PS1 and seven Wt) with low rates of complications. We confirmed that the apheresis module is permeable to the Aβ peptide and impermeable to mAb. Moreover, our results showed that continuous clearance of soluble Aβ from the CSF for a few weeks decreases cortical Aβ plaques. Thus, we conclude that this intervention is feasible and may provide important advantages in terms of safety and efficacy.This work was supported by the Instituto de Salud Carlos III, under Grant DTS19-00071 to M.M.-G. and by the Fundación para el Fomento en Asturias de la Investigación Científica Aplicada y la Tecnología (FICYT), under Grant AYUD/2021/57540, to C.T.-Z

Stigma, labeling, disrespect: Demeaning reclassifications in Goffman, Becker and Honneth

Este artículo propone una comparación teórica entre las perspectivas de Goffman, Becker y Honneth a partir del problema de las reclasificaciones sociales. Así, se focaliza en una preocupación compartida por estos autores: las reclasificaciones “degradantes”. Éstas implican modos de catalogar de manera negativa y lacerante a los individuos y grupos, con la imposición de “estigmas” (Goffman), el “etiquetamiento” de “desviados” (Becker) y el “menosprecio”, la “reificación” o la “ausencia o pérdida del reconocimiento” de individuos y grupos (Honneth). De esta manera, este trabajo da cuenta de sus propuestas destacando aquellas afinidades que comparten y que ubican a Goffman y a Becker como antecedentes ineludibles de la teoría de Honneth. Se sostiene que estas afinidades respecto de los procesos reclasificatorios y de las identidades degradantes se conectan tanto con su carácter experiencial, que involucra la afectividad y la corporalidad, como con la importancia de lo público, espacio decisivo para el despliegue de esos procesos e identidades. Además, se resalta cierto enfoque de Goffman y Becker a partir del cual es posible realizar un aporte enriquecedor a la propuesta de Honneth. Se trata de la constante negociación desplegada en los procesos reclasificatorios degradantes, en especial, en las relaciones entre el individuo y el “grupo degradado”, las cuales pueden implicar fuertes tensiones e, incluso, desgarramientos.This article proposes a theoretical comparison between the perspectives of Goffman, Becker and Honneth on the problem of social reclassifications. Thus, it focuses on a concern shared by these authors: “demeaning” reclassifications. These involve ways of negatively and laceratingly categorizing individuals and groups, with the imposition of "stigmas" (Goffman), the "labeling" of "deviants" (Becker) and the "disrespect", "reification" or "absence or loss of recognition" of individuals and groups (Honneth). In this way, this paper gives an account of their proposals highlighting those affinities that they share and that place Goffman and Becker as unavoidable antecedents of Honneth's theory. It is argued that these affinities regarding reclassifying processes and degrading identities are connected both with their experiential character, which involves affectivity and corporeality, and with the importance of the public, a decisive space for the deployment of these processes and identities. In addition, a certain approach of Goffman and Becker is highlighted, from which it is possible to make an enriching contribution to Honneth's proposal. This approach is related to the constant negotiation deployed in the degrading reclassifying processes, especially in the links between the individual and the "demeaned group", which may involve strong tensions and even tearing apart.Fil: Bialakowsky, Alejandro Marcos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; ArgentinaFil: Sasín, Mariano Gustavo. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Instituto de Investigaciones "Gino Germani"; ArgentinaFil: Nougués, Tomás. Universidad del Salvador. Facultad de Ciencias Sociales; ArgentinaFil: Zapico, Manuel. Universidad del Salvador. Facultad de Ciencias Sociales; ArgentinaFil: Barrero, Julieta. Universidad del Salvador. Facultad de Ciencias Sociales; ArgentinaFil: Ichaso, Elisa. Universidad del Salvador. Facultad de Ciencias Sociales; ArgentinaFil: Bertelli, Agustin Alejandro. Universidad del Salvador. Facultad de Ciencias Sociales; Argentin

A Multiple-Choice Maze-like Spatial Navigation Task for Humans Implemented in a Real-Space, Multipurpose Circular Arena.

Spatial navigation is a key aspect of human behavior and it is still not completely understood. A number of experimental approaches exist, although most of the published data in the last decades have relied on virtual maze on-screen simulation or not-completely freely moving 3D devices. Some interesting recent developments, such as circular mazes, have contributed to analyze critical aspects of freely moving human spatial navigation in real space, although dedicated protocols only allow for simple approaches. Here, we have developed both specifically designed and home-assembled hardware equipment, and a customized protocol for spatial navigation evaluation in freely moving humans in a real space circular arena. The spatial navigation protocol poses an imitation of a real-space multiple-choice path maze with cul-de-sac and instances of non-linear movement. We have compared the results of this system to those of a number of validated, both virtual and real, spatial navigation tests in a group of participants. The system composed by hardware, the test protocol, and dedicated measure analysis designed in our laboratory allows us to evaluate human spatial navigation in a complex maze with a small and portable structure, yielding a highly flexible, adaptable, and versatile access to information about the subjects’ spatial navigation abilities.P.M. was funded by a predoctoral fellowship (FPI) grant, PRE2020/093032, from the Ministerio de Ciencia e Innovación; E.C. was funded by a predoctoral fellowship (FPI) grant, BES-2017/080415, from the Ministerio de Economía y Competitividad; P.T. was funded by a predoctoral fellowship (FPU) grant, 18/00069, from the Ministerio de Universidades. This research received no other external specific funding