Receptor-mediated endocytosis is the main mechanism for selective transport of macromolecules into cells. Significant progress has been made in elucidating the various steps of endocytosis at the cellular level. However, the physiological relevance of many endocytic pathways for organ function remains elusive.
We study orphan endocytic receptors expressed in the central nervous system to uncover their roles during development but also in neurodegenerative diseases of the brain.
The main class of endocytic receptors is the LDL receptor gene family (Fig. 1). The prototype of the gene family is the LDL receptor that mediates uptake of cholesterol-rich lipoproteins. Since other family members also bind lipoproteins, roles for these receptors in lipid metabolism had been anticipated. Surprisingly, studies in previous years uncovered many more functions performed by these receptors, changing our perception of lipoprotein receptors from mere cargo transporters to key regulators of numerous physiological processes. In particular, the significance of these receptors for development and functional integrity of the central nervous system is noteworthy. Yet, studies so far provided just a glimpse at their contributions to neurobiology, with many details still to be uncovered.
Fig. 1: LDL receptor and sortilin gene families.
Whereas studies on the LDL receptor gene family yielded exciting insights into the significance of endocytosis for neuronal signaling, identification of another group of orphan receptors called sortilins directed our attention to the role of receptors in intracellular protein transport in neurons. The founding member of this new gene family is SORLA, a receptor that shares structural elements of the LDL receptor gene family (Fig. 1). In addition, it includes a VPS10P domain initially identified in the vacuolar protein sorting 10 protein, a sorting receptor in yeast. Subsequent identification of four other mammalian proteins that share the VPS10P domain suggested the existence of a new class of neuronal receptors that act in endocytosis and/or intracellular protein transport. Their functions remained poorly characterized.
In recent years, work from our group has significantly contributed to a deeper understand of the role of endocytic receptors in normal physiological processes and in inherited diseases of the human brain. Specifically, we focused on three receptors, namely LRP2, SORLA, and sortilin.
For example, we demonstrated that LRP2, a member of the LDL receptor gene family, acts as receptor for sonic hedgehog (SHH) and is required for cellular trafficking and signaling of this morphogen in the mammalian forebrain. Lack of LRP2 activity in mouse models and in patients results in forebrain malformation and in holoprosencephaly.
We showed that SORLA is a receptor for the amyloid precursor protein (APP) that impairs intracellular transport and processing to the amyloid β-peptide, the main constituent of senile plaques. We uncovered the molecular mechanisms that govern SORLA-dependent trafficking of APP in neurons, and we identified receptor gene variants that cause decreased levels of receptor expression and that predispose carriers to risk of sporadic Alzheimer’s disease (AD). Finally, we provided proof of concept that raising brain SORLA levels represents a novel therapeutic approach in AD.
Concerning sortilin, we identified its role as receptor for neurotrophins in control of neuronal viability and function during ageing and in degenerative processes of the nervous system; and we demonstrated the ability of this protein to control hepatic release of lipoproteins, suggesting an intriguing link between lipid metabolism and neurodegeneration.
More details on these projects can be found here: