Overexpression of guanylate cyclase activating protein 2 in rod photoreceptors in vivo leads to morphological changes at the synaptic ribbon

Guanylate cyclase activating proteins are EF-hand containing proteins that confer calcium sensitivity to retinal guanylate cyclase at the outer segment discs of photoreceptor cells. By making the rate of cGMP synthesis dependent on the free intracellular calcium levels set by illumination, GCAPs play a fundamental role in the recovery of the light response and light adaptation. The main isoforms GCAP1 and GCAP2 also localize to the synaptic terminal, where their function is not known. Based on the reported interaction of GCAP2 with Ribeye, the major component of synaptic ribbons, it was proposed that GCAP2 could mediate the synaptic ribbon dynamic changes that happen in response to light. We here present a thorough ultrastructural analysis of rod synaptic terminals in loss-of-function (GCAP1/GCAP2 double knockout) and gain-of-function (transgenic overexpression) mouse models of GCAP2. Rod synaptic ribbons in GCAPs−/− mice did not differ from wildtype ribbons when mice were raised in constant darkness, indicating that GCAPs are not required for ribbon early assembly or maturation. Transgenic overexpression of GCAP2 in rods led to a shortening of synaptic ribbons, and to a higher than normal percentage of club-shaped and spherical ribbon morphologies. Restoration of GCAP2 expression in the GCAPs−/− background (GCAP2 expression in the absence of endogenous GCAP1) had the striking result of shortening ribbon length to a much higher degree than overexpression of GCAP2 in the wildtype background, as well as reducing the thickness of the outer plexiform layer without affecting the number of rod photoreceptor cells. These results indicate that preservation of the GCAP1 to GCAP2 relative levels is relevant for maintaining the integrity of the synaptic terminal. Our demonstration of GCAP2 immunolocalization at synaptic ribbons at the ultrastructural level would support a role of GCAPs at mediating the effect of light on morphological remodeling changes of synaptic ribbons.

Phosphorylated α-synuclein-immunoreactive retinal neuronal elements in Parkinson's disease subjects

Visual symptoms are relatively common in Parkinson's disease (PD) and optical coherence tomography has indicated possible retinal thinning. Accumulation of aggregated α-synuclein is thought to be a central pathogenic event in the PD brain but there have not as yet been reports of retinal synucleinopathy. Retinal wholemounts were prepared from subjects with a primary clinicopathological diagnosis of PD (N = 9), dementia with Lewy bodies (DLB; N = 3), Alzheimer's disease (N = 3), progressive supranuclear palsy (N = 2) as well as elderly normal control subjects (N = 4). These were immunohistochemically stained with an antibody against α-synuclein phosphorylated at serine 129, which is a specific molecular marker of synucleinopathy. Phosphorylated α-synuclein-immunoreactive (p-syn IR) nerve fibers were present in 7/9 PD subjects and in 1/3 DLB subjects; these were sparsely distributed and superficially located near or at the inner retinal surface. The fibers were either long and straight or branching, often with multiple en-passant varicosities along their length. The straight fibers most often had an orientation that was radial with respect to the optic disk. Together, these features are suggestive of either retinopetal/centrifugal fibers or of ganglion cell axons. In one PD subject there were sparse p-syn IR neuronal cell bodies with dendritic morphology suggestive of G19 retinal ganglion cells or intrinsically photosensitive ganglion cells. There were no stained nerve fibers or other specific staining in any of the non-PD or non-DLB subjects. It is possible that at least some of the observed visual function impairments in PD subjects might be due to α-synucleinopathy.

Desigualdades de género en la investigación en salud pública y epidemiología en España (2007-2014)

Objetivo: Analizar las desigualdades de género en investigación en salud pública y epidemiología en España, en el periodo 2007-2014. Método: Estudio descriptivo según sexo de posiciones de liderazgo del Centro de Investigación Biomédica en Red (CIBER), especialmente en el área temática de epidemiología y salud pública (CIBERESP) en 2014; de sociedades científicas de salud pública (SESPAS) y epidemiología (SEE), 2009-2014; y de proyectos de investigación solicitados (13.320) y financiados (4699), e importes de convocatorias de Acción Estratégica en Salud (AES), 2007-2013. Resultados: Existe una clara infrarrepresentación de mujeres líderes y contratadas en investigación de excelencia en salud pública (CIBERESP), con predominio de los hombres en puestos de decisión. Aunque los proyectos de investigación de la Acción Estratégica en Salud (AES) liderados por mujeres han crecido ligeramente entre 2007 y 2013, entre los solicitados no alcanzan el 50%, con excepción de los de la Comisión de Salud Pública. La brecha de género es aún mayor en proyectos financiados. Los proyectos liderados por hombres tienen mayor probabilidad de obtener financiación, alcanzando el 29% en los de salud pública. Persiste una segregación horizontal de género en posiciones de reconocimiento científico en congresos de SESPAS y SEE. Conclusiones: La sobrerrepresentación de líderes masculinos en la investigación en salud pública en España debe entenderse como indicador y consecuencia del androcentrismo en las sociedades científicas y los grupos profesionales. Esta situación sexista pone en riesgo la existencia de productos y servicios innovadores desde la perspectiva de género que den respuestas a necesidades y demandas de toda la sociedad. Se necesitan más mujeres en investigación que tengan incorporada esta perspectiva.