Expression, Subcellular Localization, and Mechanistic Analysis of Intellectual Disability Syndrome Protein ABBA

A missense mutation in the MTSS2 gene, which encodes the I-BAR domain protein ABBA (Mtss1l/Mtss2), has been linked to an intellectual disability syndrome. To better understand the MTSS2 mutation-related effect in the brain, we elucidated the cells expressing ABBA and the localization of ABBA in these cells to get insights into which cells and processes might be dysfunctional in mutation-carrying patients. As a novel discovery, we found that ABBA was highly expressed in GABAergic inhibitory neurons, such as parvalbumin-positive interneurons in the hippocampus. At the subcellular level, ABBA localizes to the edges of membrane protrusions in various cells in the brain, suggesting a role in cell migration and spinogenesis. Overexpression of ABBA in pyramidal excitatory and inhibitory neurons increased dendritic spine density. Through live-cell imaging, we demonstrated that ABBA facilitates spine initiation by clustering on the plasma membrane before a new filopodium appears. However, our live cell imaging data also revealed that ABBA localized not only to small focal points, typical for filopodia formation, on the plasma membrane, but also more broadly on the edge of lamellipodial structures. Compared to its close homolog MIM, ABBA appears to be a more general facilitator of protrusion formation, from dendritic filopodia to lamellipodial structures. Altogether, our findings provide insights into ABBA expression, localization, and functional mechanisms, advancing our understanding of its role in neurodevelopmental processes and disorders.