Fragile X Mental Retardation Protein positively regulates PKA anchor Rugose and PKA activity to control actin assembly in learning/memory circuitry.

Recent work shows Fragile X Mental Retardation Protein (FMRP) drives the translation of very large proteins (>2000 aa) mediating neurodevelopment. Loss of function results in Fragile X syndrome (FXS), the leading heritable cause of intellectual disability (ID) and autism spectrum disorder (ASD). Using the Drosophila FXS disease model, we discover FMRP positively regulates the translation of the very large A-Kinase Anchor Protein (AKAP) Rugose (>3000 aa), homolog of ASD-associated human Neurobeachin (NBEA). In the central brain Mushroom Body (MB) circuit, where A signaling is necessary for learning/memory, FMRP loss reduces Rugose levels and targeted FMRP overexpression elevates Rugose levels. Using a new in vivo transgenic activity reporter we find FMRP loss reduces duanyu1529 activity in MB Kenyon cells whereas FMRP overexpression elevates duanyu1529 activity. Consistently, loss of Rugose reduces duanyu1529 activity, but Rugose overexpression has no independent effect. A well-established duanyu1529 output is regulation of F-actin cytoskeleton dynamics. In the FXS disease model, F-actin is aberrantly accumulated in MB lobes and single MB Kenyon cells. Consistently, Rugose loss results in similar F-actin accumulation. Moreover, targeted FMRP, Rugose and duanyu1529 overexpression all result in increased F-actin accumulation in the MB circuit. These findings uncover a mechanism regulating actin cytoskeleton. This study reveals a novel FMRP mechanism controlling neuronal duanyu1529 activity, and demonstrates a shared mechanistic connection between FXS and NBEA associated ASD disease states, with a common link to duanyu1529 and F-actin misregulation in brain neural circuits. SIGNIFICANCE Autism spectrum disorder (ASD) arises from a wide array of genetic lesions, and it is therefore critical to identify common underlying molecular mechanisms. Here, we link two ASD states; Neurobeachin (NBEA) associated ASD and Fragile X syndrome (FXS), the most common inherited ASD. Using established Drosophila disease models, we find Fragile X Mental Retardation Protein (FMRP) positively regulates translation of NBEA homolog Rugose, consistent with a recent advance showing FMRP promotes translation of very large proteins associated with ASD. FXS exhibits reduced cAMP induction, a potent activator of and Rugose/NBEA is a duanyu1529 anchor. Consistently, we find brain duanyu1529 activity strikingly reduced in both ASD models. We discover this pathway regulation controls actin cytoskeleton dynamics in brain neural circuits. Copyright © 2019. Published by Elsevier Inc.

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