Intersectins as versatile scaffolds for membrane-associated processes

Intersectins with their numerous protein interaction domains serve as versatile scaffolds for a range of membrane-associated processes. While being originally characterized as endocytic proteins, their functions clearly extend beyond the scaffolding of endocytic machinery. By interacting with and stabilizing important cellular signaling components, ranging from neurotransmitter receptors to complexes involved in neuronal guidance, intersectins play a key role in shaping neuronal processes. Consequently, intersectin deficiency in model organisms causes the most severe impairments in the brain, illustrating their crucial function for neuronal development and neurotransmission. In line with this, mutations in the human gene encoding intersectin 1 (ITSN1) have been linked to neurodevelopmental and neuropsychiatric disorders. In addition, haploinsufficiency of ITSN1 has recently been associated with an increased risk of Parkinson´s disease. In this review, we will discuss our current knowledge regarding the molecular functions of intersectins in order to better understand the pathological consequences of intersectin deficiency.