ABSTRACT
Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by decreased levels of the survival of motoneuron (SMN) protein. Post-translational mechanisms for regulation of its stability are still elusive. Thus, we aimed to identify regulatory phosphorylation sites that modulate function and stability. Our results show that SMN residues S290 and S292 are phosphorylated, of which SMN pS290 has a detrimental effect on protein stability and nuclear localization. Furthermore, we propose that phosphatase and tensin homolog (PTEN), a novel phosphatase for SMN, counteracts this effect. In light of recent advancements in SMA therapies, a significant need for additional approaches has become apparent. Our study demonstrates S290 as a novel molecular target site to increase the stability of SMN. Characterization of relevant kinases and phosphatases provides not only a new understanding of SMN function, but also constitutes a novel strategy for combinatorial therapeutic approaches to increase the level of SMN in SMA.
Subject(s)
Amino Acids/metabolism , PTEN Phosphohydrolase/metabolism , Survival of Motor Neuron 1 Protein/chemistry , Survival of Motor Neuron 1 Protein/metabolism , Amino Acid Sequence , Animals , Caenorhabditis elegans , Cell Line, Tumor , Cell Nucleus/metabolism , Gene Knockdown Techniques , Humans , Mice , Mutant Proteins/chemistry , Mutant Proteins/metabolism , Phosphorylation , Phosphoserine/metabolism , Proteasome Endopeptidase Complex/metabolism , Protein Binding , Protein Stability , Proteolysis , Structure-Activity RelationshipABSTRACT
Objective: Detection and identification of moving targets is of paramount importance in everyday life, even if it is not widely tested in optometric practice, mostly for technical reasons. There are clear indications in the literature that in perception of moving targets, vision and hearing interact, for example in noisy surrounds and in understanding speech. The main aim of visual perception, the ability that optometry aims to optimize, is the identification of objects, from everyday objects to letters, but also the spatial orientation of subjects in natural surrounds. To subserve this aim, corresponding visual and acoustic features from the rich spectrum of signals supplied by natural environments have to be combined. Methods: Here, we investigated the influence of an auditory motion stimulus on visual motion detection, both with a concrete (left/right movement) and an abstract auditory motion (increase/decrease of pitch). Results: We found that incongruent audiovisual stimuli led to significantly inferior detection compared to the visual only condition. Additionally, detection was significantly better in abstract congruent than incongruent trials. For the concrete stimuli the detection threshold was significantly better in asynchronous audiovisual conditions than in the unimodal visual condition. Conclusion. We find a clear but complex pattern of partly synergistic and partly inhibitory audio-visual interactions. It seems that asynchrony plays only a positive role in audiovisual motion while incongruence mostly disturbs in simultaneous abstract configurations but not in concrete configurations. As in speech perception in hearing-impaired patients, patients suffering from visual deficits should be able to benefit from acoustic information (AU)
Objetivo: La detección e identificación de los objetivos en movimiento es de extrema importancia en la vida diaria, aun cuando no se ha probado ampliamente en la práctica optométrica por motivos técnicos. La literatura incluye indicaciones claras acerca de la interacción entre la percepción de objetivos en movimiento, la visión y la audición, como por ejemplo en los ambientes ruidosos y en la comprensión del habla. La meta principal de la percepción visual, la capacidad que trata de optimizar la optometría, es la identificación de objetos, desde los cotidianos a las letras, y también la orientación espacial de los sujetos en entornos naturales. Para ayudar a lograr esta meta, deben combinarse las correspondientes características visuales y acústicas de entre el amplio espectro de señales que aportan los ambientes naturales. Métodos: Investigamos la influencia de un estímulo de movimiento auditivo sobre la detección del movimiento visual, tanto en el movimiento auditivo concreto (movimiento izquierda/derecha) como abstracto (incremento/decremento de tono). Resultados: Encontramos que los estímulos audiovisuales incongruentes originaban una detección significativamente inferior en comparación a la situación únicamente visual. Además, la detección fue considerablemente mejor en los campos congruentes abstractos que en los incongruentes. Para los estímulos concretos, el umbral de detección fue significativamente inferior en situaciones audiovisuales asíncronas que en la situación visual unimodal. Conclusión: Encontramos un patrón claro aunque complejo de interacciones audio-visuales parcialmente sinérgicas y parcialmente inhibitorias. Parece ser que la asincronía juega únicamente un papel positivo en el movimiento audiovisual, mientras que la incongruencia se altera principalmente en las configuraciones abstractas simultáneas pero no en las configuraciones concretas. Como en la percepción del habla en pacientes con deficiencias auditivas, los pacientes que padecen déficits visuales deberían poder beneficiarse de la información acústica (AU)
Subject(s)
Humans , Male , Female , Adult , Optometry/methods , Vision Disorders , Visual Perception/radiation effects , Psychophysics/methods , Healthy Volunteers/statistics & numerical data , Data Analysis/methods , Analysis of VarianceABSTRACT
OBJECTIVE: Detection and identification of moving targets is of paramount importance in everyday life, even if it is not widely tested in optometric practice, mostly for technical reasons. There are clear indications in the literature that in perception of moving targets, vision and hearing interact, for example in noisy surrounds and in understanding speech. The main aim of visual perception, the ability that optometry aims to optimize, is the identification of objects, from everyday objects to letters, but also the spatial orientation of subjects in natural surrounds. To subserve this aim, corresponding visual and acoustic features from the rich spectrum of signals supplied by natural environments have to be combined. METHODS: Here, we investigated the influence of an auditory motion stimulus on visual motion detection, both with a concrete (left/right movement) and an abstract auditory motion (increase/decrease of pitch). RESULTS: We found that incongruent audiovisual stimuli led to significantly inferior detection compared to the visual only condition. Additionally, detection was significantly better in abstract congruent than incongruent trials. For the concrete stimuli the detection threshold was significantly better in asynchronous audiovisual conditions than in the unimodal visual condition. CONCLUSION: We find a clear but complex pattern of partly synergistic and partly inhibitory audio-visual interactions. It seems that asynchrony plays only a positive role in audiovisual motion while incongruence mostly disturbs in simultaneous abstract configurations but not in concrete configurations. As in speech perception in hearing-impaired patients, patients suffering from visual deficits should be able to benefit from acoustic information.
