New aspects of a small GTPase RAB35 in brain development and function.

In eukaryotic cells, organelles in the secretory, lysosomal, and endocytic pathways actively exchange biological materials with each other through intracellular membrane trafficking, which is the process of transporting the cargo of proteins, lipids, and other molecules to appropriate compartments via transport vesicles or intermediates. These processes are strictly regulated by various small GTPases such as the RAS-like in rat brain (RAB) protein family, which is the largest subfamily of the RAS superfamily. Dysfunction of membrane trafficking affects tissue homeostasis and leads to a wide range of diseases, including neurological disorders and neurodegenerative diseases. Therefore, it is important to understand the physiological and pathological roles of RAB proteins in brain function. RAB35, a member of the RAB family, is an evolutionarily conserved protein in metazoans. A wide range of studies using cultured mammalian cells and model organisms have revealed that RAB35 mediates various processes such as cytokinesis, endocytic recycling, actin bundling, and cell migration. RAB35 is also involved in neurite outgrowth and turnover of synaptic vesicles. We generated brain-specific Rab35 knockout mice to study the physiological roles of RAB35 in brain development and function. These mice exhibited defects in anxiety-related behaviors and spatial memory. Strikingly, RAB35 is required for the precise positioning of pyramidal neurons during hippocampal development, and thereby for normal hippocampal lamination. In contrast, layer formation in the cerebral cortex occurred superficially, even in the absence of RAB35, suggesting a predominant role for RAB35 in hippocampal development rather than in cerebral cortex development. Recent studies have suggested an association between RAB35 and neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. In this review, we provide an overview of the current understanding of subcellular functions of RAB35. We also provide insights into the physiological role of RAB35 in mammalian brain development and function, and discuss the involvement of RAB35 dysfunction in neurodegenerative diseases.