the other hand in the retention of new memory traces in the hippocampal formation. vldlr links the reelin protein to an intracellular signaling protein, dab1, that tells the individual neurons where to go within the anatomy of the brain. mutations in vldlr often do not lead to major disorganization as seen in reelin mutations. however, a vldlr mutation does lead to some disorganization primarily located in the cerebellum, where vldlr is believed to be most prominent. neuronal migration vldlr is expressed on migrating neurons to help guide them to their proper location in the brain. this process is part of the reelin pathway, which is responsible for the inside-out formation of the six-layered neocortex. despite the discovery of this pathway, many of the specifics and molecular mechanisms of this process are still being debated. the presence of two reelin receptors, vldlr and apoer2, has made it difficult to distinguish each protein’s specific function. organization of the six layered neocortex. in the absence of vldlr, the neuroblasts of the cortical plate invade the marginal zone above. vldlr is primarily responsible for the correct layering of pyramidal cells into layer 1 of the cerebral cortex. in particular, the absence of vldlr may lead to ectopic accumulation of pyramidal cells in this region. vldlr does not affect the migration of early born cells into an organized layer, but since its absence results in the invasion of these neuroblasts into the marginal zone, it is theorized that vldlr may encode a “stop signal.” this is supported by the fact that vldlr is primarily expressed in the cortical plate adjacent to reelin-expressing cells, cajal–retzius cells, and in the intermediate zone. however, definitive evidence has not yet been found. in general, reelin binds vldlr and undergoes endocytosis via clathrin-coated vesicles. meanwhile, an intracellular protein, dab1, has a pi/ptb domain that interacts with the npxy sequence found in the cytoplasmic tail of vldlr. as a result, dab1 is tyrosine phosphorylated and reelin is degraded. finally, phosphorylated dab1 activates an intracellular signaling cascade that directs neuroblasts to their proper location through the alteration of the cytoskeleton. many of the specifics of this pathway are still being investigated. it is not yet known if dab1 is phosphorylated as a result of the endocytosis of reelin, or if there is another mechanism at play. in addition to the organization of the neocortex, vldlr also plays a role in neuronal migration of the hippocampus and the purkinje cells of the cerebellum. yet, much information on this process is still unknown. associated disorders mutations within the vldlr gene lead to a multitude of disorders of varying severities. these disorders are usually associated with cholesterol homeostasis or a disorganization of neuron ordering in the brain due to disruption of the reelin pathway. the most prominent of these diseases are type i lissencephaly, vldr-associated cerebellar hypoplasia, and atherosclerosis. in contrast to causing diseases, vldlr has also been identified as a possible remedy for some disorders. implementation of vldlr into the liver may cure familial hypercholesterolemia (fh) in patients who either have defective ldlr or have defective immune systems that attack this protein. since vldlr is non-immunogenic it does not initiate an immune response, thus it is able to function normally under defective immune systems. in addition, being that apoe, a major ligand of vldlr, is a leading genetic risk factor for alzheimer’s disease, vldlr may play a role in modulating the risk of this disorder which is explained by the fact that a decrease in reelin signaling in the fascia dentata is supposed to initiate alzheimer's disease. vldlr has also been shown to reduce the chances of premature heart disease and stroke because vldlr clears out lipoprotein a (lp(a)), a major inherited risk factor for these diseases. type 1 lissencephaly type i lissencephaly, or agyria-pachygyria, is a rare developmental disorder characterized by the absence of gyri and sulci in the brain. these severe malformations are a result of aberrant neuronal migration. in classical type i lissencephaly, neuronal migration begins but is unable to continue to completion. this process is likely disrupted by alterations to several genes, including the vldlr, dcx, arx, tuba1a, reln and lis1. the severity of type i lissencephaly therefore varies with the mutation type. a homozygous deletion affecting the vldlr gene results in a low degree of cortical thickening and absence of a cell-sparse zone. the cell-sparse zone describes the region between the outer and inner cortical layers of arrested neurons. in addition, type 1 lissencephaly is closely associated with cerebellar hypoplasia. vldlr-associated cerebellar hypoplasia disequilibrium syndrome (des) was first described in the 1970s as a non-progressive, neurological disorder. in a 2005 study, des was renamed as vldlr-associated cerebellar hypoplasia (vldlrch) after its cause was linked to a disruption in the vldlr gene. at least six mutations affecting the homozygous recessive allele of the vldlr gene have been identified and found to cause vldlrch. several of these mutations have been localized to specific exons encoding the gene. one such mutation is a cytosine to thymine transition at base pair 1342 in exon 10 that causes a substitution at arg448 for a termination signal. likewise, there is evidence of a cytosine to thymine transition at base pair number 769 in exon 5 that causes a substitution at arg257 for a termination signal. a third known mutation is caused by a homozygous 1-base pair deletion in exon 17 that causes a frameshift and premature termination in the o-linked sugar domain. all such alterations to the vldlr gene prevent the production of vldlr and are therefore termed loss-of-function mutations. the recognized symptoms of vldlrch are moderate-to-severe intellectual disability, seizures, dysarthria, strabismus and delayed locomotion. in some cases, children with vldlrch learn to walk very late in development after the age of six years, or never learn to walk independently. the frequency of this disorder is unknown because early diagnosis of vldlrch is difficult using imaging techniques. it is associated with parental consanguinity and found in secluded communities such as the hutterites and inbred families from iran and turkey. atherosclerosis atherosclerosis is marked by an excessive accumulation of cholesterol by macrophages, leading to their transformation into foam cells. this accumulation of cholesterol is caused by dysregulation of cholesterol influx and efflux. since macrophages do not have the ability to limit the influx of cholesterol, the balance is completely dependent on efflux pathways. vldlr is expressed by macrophages, and functions in the uptake of native lipoproteins. uniquely, vldlr does not respond to cholesterol loading, likely due to its lack of feedback mechanisms. the inability to control its uptake of native lipoproteins makes vldlr a pro-atherogenic factor. this characteristic is supported by results from a 2005 study, in which reintroduction of vldlr into vldlr knockout mice led to greatly increased atherosclerotic lesion development.