Lysosomal membrane permeabilization and autophagy blockade contribute to photoreceptor cell death in a mouse model of retinitis pigmentosa.

Retinitis pigmentosa is a group of hereditary retinal dystrophies that normally result in photoreceptor cell death and vision loss both in animal models and in affected patients. The rd10 mouse, which carries a missense mutation in the Pde6b gene, has been used to characterize the underlying pathophysiology and develop therapies for this devastating and incurable disease. Here we show that increased photoreceptor cell death in the rd10 mouse retina is associated with calcium overload and calpain activation, both of which are observed before the appearance of signs of cell degeneration. These changes are accompanied by an increase in the activity of the lysosomal protease cathepsin B in the cytoplasm of photoreceptor cells, and a reduced colocalization of cathepsin B with lysosomal markers, suggesting that lysosomal membrane permeabilization occurs before the peak of cell death. Moreover, expression of the autophagosomal marker LC3-II (lipidated form of LC3) is reduced and autophagy flux is blocked in rd10 retinas before the onset of photoreceptor cell death. Interestingly, we found that cell death is increased by the induction of autophagy with rapamycin and inhibited by calpain and cathepsin inhibitors, both ex vivo and in vivo. Taken together, these data suggest that calpain-mediated lysosomal membrane permeabilization underlies the lysosomal dysfunction and downregulation of autophagy associated with photoreceptor cell death.

Autophagy promotes survival of retinal ganglion cells after optic nerve axotomy in mice.

Autophagy is an essential recycling pathway implicated in neurodegeneration either as a pro-survival or a pro-death mechanism. Its role after axonal injury is still uncertain. Axotomy of the optic nerve is a classical model of neurodegeneration. It induces retinal ganglion cell death, a process also occurring in glaucoma and other optic neuropathies. We analyzed autophagy induction and cell survival following optic nerve transection (ONT) in mice. Our results demonstrate activation of autophagy shortly after axotomy with autophagosome formation, upregulation of the autophagy regulator Atg5 and apoptotic death of 50% of the retinal ganglion cells (RGCs) after 5 days. Genetic downregulation of autophagy using knockout mice for Atg4B (another regulator of autophagy) or with specific deletion of Atg5 in retinal ganglion cells, using the Atg5(flox/flox) mice reduces cell survival after ONT, whereas pharmacological induction of autophagy in vivo increases the number of surviving cells. In conclusion, our data support that autophagy has a cytoprotective role in RGCs after traumatic injury and may provide a new therapeutic strategy to ameliorate retinal diseases.

Alteraciones de los fenómenos de neuroplasticidad en las enfermedades de Alzheimer y Creutzfeldt-Jakob. Interrelaciones con fenómenos involutivos / Neuroplasticity changes in Alzheimer´s and Creutztfeldt-Jakob´s Diseases. Relationships to involutive phenomena

Se ha postulado que en las enfermedades neurodegenerativas,las alteraciones en los fenómenos de neuroplasticidady adaptación tienen una función muy importante,como desencadenante o motor del curso patogénico delas enfermedades. Para aclarar este extremo se ha llevadoa cabo un estudio morfohistoquímico comparativo en lacorteza cerebral prefrontal y en la corteza cerebelosa(neocerebelo) de cerebros de enfermos de Alzheimer yCreutzfeldt-Jakob (EA y ECJ). Se han analizado las variacionesen marcadores supuestamente relacionados confenómenos de neuroplasticidad sináptica (Drebrina, SNAP-25), factor de activación nuclear (NF kappa Beta -NFkB) eisoforma neuronal de la óxido nítrico sintasa (nNOS) juntoa marcardores de neuropatología (acumulación de proteínasbeta –amiloide en EA y PrPsc en ECJ-, reacción microgliale inducción de enzimas pro-inflamatorias iNOS yciclo-oxigenasa 2 (COX-2). Los resultados han mostradograndes variaciones de los marcadores entre ambos procesospatológicos, entre las cortezas cerebral y cerebelosa,entre diferentes áreas de esas regiones y entre diferentesestirpes neuronales y gliales. El significado de algunosde los marcadores (NFkB, nNOS, proteínas sinápticas) puede ser variable (plástico o involutivo) según los casos(enfermedad, región, factores). La neuroplasticidad disminuyede manera diversa según las áreas cerebrales y susrelaciones con las manifestaciones neuropatológicas tambiénson variables, aunque son manifiestos fenómenos deneuroplasticidad/adaptación en muchas áreas y neuronas.Se concluye que la activación de los supuestos marcadoresde neuroplasticidad en fases avanzadas de la enfermedad,con una idea terapéutica, puede activar fenómenosinvolutivos en algunas regiones o neuronas del cerebro

Changes in neuroplasticity and neuronal adaptativemechanisms have been postulated as origin and/or mainpathophysiological factor in neurodegenerative diseases.To analyze these theories, a comparative morphohistochemicalstudy on the cerebral (prefrontal) and cerebellar(neocerebellar) cortex from Alzheimer´s (AD) and Creutzfeldt-Jakob (CJD) post-mortem brains has been carriedout. Variations in putative markers of neuroplasticity andneuronal adaptation (synaptic proteins such as drebrinand SNAP-25; nuclear factor NF kappa Beta –NFkB-; neuronalisoform of oxide nitric synthase -nNOS) have beenstudied in close association with neuropathological markers(beta-protein deposition – amyloid in AD and PrPsc inCJD-; microglial activation, induction of iNOS and cyclooxygenase2 –COX-2). Results have shown sharp variationsin these markers when compared AD and CJD; cerebraland cerebellar cortex; different areas of these anatomicalregions; and different sets of neurons and glial cells.The meaining of somme of these markers (NFkB; nNOS;synaptic proteins) could be variable (plastic/adaptative orinvolutive), depending on different factors (disease, anatomicalregion, general or local factors, etc.). Neuroplasticity is evident in several brain regions or neurons, but this neuronalfeature decreases in different form depending alsoon the disease and the anatomical region. Their relationshipsto the neuropathological findings were also variable.In conclusion, the activation of these putative markers ofneuroplasticity, considering as therapeutical targets, inadvanced steps of the diseases, could activate neuronalinvolutive phenomena in several regions or neurons