Sandkuhler, S. | bioRxiv Science

bioRxiv2023

BAG3 regulates the specificity of the recognition of specific MAPT species by NBR1 and SQSTM1

Autophagy receptors are essential for the recognition and clearance of specific cargos by selective autophagy, which is essential for maintaining MAPT proteostasis. Previous studies have implicated different autophagy receptors in directing distinct species of MAPT to autophagy, but the underlying mechanisms have not been fully investigated. Here we examine how the autophagy receptors NBR1 and SQSTM1 differentially engage specific forms of MAPT and facilitate their clearance. In primary neurons depletion of NBR1, unlike depletion of SQSTM1, significantly increased phosphorylated MAPT levels. The specificity of the interactions were confirmed using in vitro binding assays with purified proteins. We provide direct evidence that NBR1 preferentially binds to monomeric MAPT, while SQSTM1 interacts predominantly with oligomeric MAPT, and that the co-chaperone BAG3 regulates the specificity of these interactions. Using an in vitro pulldown assay, we show that SQSTM1 only binds to monomeric MAPT when BAG3 is absent and fails to bind when BAG3 is present. The opposite is true of NBR1; its binding to monomeric MAPT was dependent on the presence of BAG3. Interestingly, in Alzheimers disease brain the association of NBR1 with BAG3 was significantly decreased. In a mouse model, ablation of BAG3 in neural cells disrupted the association of NBR1 with phosphorylated MAPT and lead to increased levels of phosphorylated and oligomeric MAPT. Overall, our results uncover a novel role for BAG3 in regulating the specificity of selective autophagy receptors in targeting different species of MAPT and provide compelling evidence that BAG3 plays a key role in maintaining MAPT proteostasis. HighlightsO_LIFirst direct evidence of the district role of NBR1 and SQSTM1 in binding with monomeric and oligomeric MAPT, respectively. C_LIO_LIDemonstration of a novel mechanism by which BAG3 regulates the specificity of the recognition of monomeric MAPT by NBR1 and oligomeric MAPT by SQSTM1. C_LIO_LIConditional knockout of BAG3 in the brain disrupted the association of NBR1 with phosphorylated MAPT and lead to increased levels of phosphorylated and oligomeric MAPT. C_LI

neuroscience↗

bioRxiv2020

Causally Linking Neural Dominance to Perceptual Dominance in a Multisensory Conflict

When different senses are in conflict, one sense may dominate the perception of other sense, but it is not known whether the sensory cortex associated with the dominant modality exerts directional influence, at the functional brain level, over the sensory cortex associated with the dominated modality; in short, the link between sensory dominance and neuronal dominance is not established. In a task involving audio-visual conflict, using magnetoencephalography recordings in humans, we first demonstrated that the neuronal dominance - visual cortex being functionally influenced by the auditory cortex - was associated with the sensory dominance - participants visual perception being qualitatively altered by sound. Further, we found that prestimulus auditory-to-visual connectivity could predict the perceptual outcome on a trial-by-trial basis. Subsequently, we performed an effective connectivity-guided neurofeedback electroencephalography experiment and showed that participants who were briefly trained to increase the neuronal dominance from auditory to visual cortex also showed higher sensory, i.e. auditory, dominance during the conflict task immediately after the training. The results shed new light into the interactive neuronal nature of multisensory integration and open up exciting opportunities by enhancing or suppressing targeted mental functions subserved by effective connectivity.

neuroscience↗