. Genome-wide screen identifies rs646776 near sortilin as a regulator of progranulin levels in human plasma. Am J Hum Genet. 2010 Dec 10;87(6):890-7. PubMed.

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  1. I see the sortilins as gateways to an enormously complex method of regulation. Various members of the sortilin family can interact with either proneurotrophins or neurotrophin receptors and determine life-versus-death pathways. SorCS1/SorL1/APP complexes are in this mix, as are sortilin/progranulin interactions defined by Strittmatter. It is likely that multiple other family members can substitute for, or add onto, these complexes. To make matters even more complex, all the sortilins are γ-secretase substrates and undergo ectodomain shedding (usually by α-secretase). That may well convert them into diffusible ligands that activate yet undiscovered sortilin ectodomain receptors.

    To add one more layer of complexity, SorL1/SorLA/LR11 is a member of both the sortilin family and the LDLR/LRP family, so that regulation by lipoproteins might also pertain.

    It is somewhat surprising that members of the sortilin family are linked to both AD and FTD, and sortilin itself is a major risk for atherosclerosis (see Musunuru et al., 2010). One the one hand, this smacks of "too much good news"; on the other hand, the genetic linkages are solid, and the challenge now is to define the molecular neurobiology of sortilins and work out how they fit into the major human diseases of AD, FTD, diabetes, and atherosclerosis.

    References:

    . From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature. 2010 Aug 5;466(7307):714-9. PubMed.