Sortilin-related receptor and Alzheimer’s disease Luke Lopas Genetics 677 4/30/09

Overview Intro to AD SORL1 Semester Results Evidence for SORL1 in AD Semester Results The future - “To boldly go where no man has gone before” Image from http://www.ghi.com/yourhealth/encyclopedia/articles/alzheimers_basics.html

What is AD? Most common form of dementia Neural Degeneration Progressive Between 2.5 and 4.5 million affected Americans Movie: What strikes me? How young the people were, and how he didn’t want to be 1/2 a person Picture: Cortex and hippocampus shrivel - hippocampus is vital in formation and storage of memories, and also the ventricles increase in size http://www.youtube.com/watch?v=76P6Xm3WsEM Image from http://www.alz.org/brain/09.asp

What does SORL1 do? Interacts with amyloid precursor protein (APP) to determine pathway used for processing Decrease in SORL1 leads to more APP entering Late Endosomal Pathway - which leads to more precursors of AD plaques. SORL1 Image from Rogaeva, E., et. al. (2007) The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nature Genetics, 39 (2).

Evidence for this role Dodson, S.E. et. al. J. Neurosci. 2008;28:12877-12886

Dodson Continued Significant correlation between: 1)Lr11 levels 2)amyloid beta levels 3)amyloid beta plaque density, and plaque count Dodson, S.E. et. al. J. Neurosci. 2008;28:12877-12886

SORL1 Stats Gene Accession #: NC_000011.8 Total Base Pairs: 177,492 Total AA: 2,214
 Location: 11q23.2-q24.2 Limited by most programs only accepting 60,000 base pairs. Limited and frustrated by DNA searching technology as that is where most of the keys lie and couldn’t find much useful info. SORL1 discovered in a GWAS and it turns out the significant SNPs were located in intronic regions. It is believed that these regions are largely responsible for the regulation of expression. Image generated from a MEME search. Timothy L. Bailey and Charles Elkan, "Fitting a mixture model by expectation maximization to discover motifs in biopolymers", Proceedings of the Second International Conference on Intelligent Systems for Molecular Biology, pp. 28-36, AAAI Press, Menlo Park, California, 1994.

Gene Ontology Biological Process: receptor-mediated endocytosis Cellular Component: integral to plasma membrane Molecular Function: low-density lipoprotein binding and transmembrane receptor activity. Image from the Gene Ontology

Protein Domains Human Domains: VPS10, LY, EGF, Ldla, FN3 Mouse Mouse shown because best experimental model. Most other homologs are very similar with exception of Rat, is a little different, none of the LY domains and in their place 4 or 5 transmembrane domains Mouse Images retrieved from SMART. Schultz et al. (1998) Proc. Natl. Acad. Sci. USA 95, 5857-5864

Homology and Phylogeny Image from TreeDyn Both used ClustalW alignments I tend to trust the bottom one more as the Rat SORL1 was the only one that really varied much from the humans, but it could be that the sequences were so similar neither program knew exactly where to throw the Rat into the mix. Image from TreeTop

Going forward We need to better understand the interaction between SORL1 and APP and other players in the pathway! What else besides SORL1 is important for AD? What controls expression levels of SORL1? Evidence that intronic sequences important, especially in cell specific expression Specifically, while there is a degrease in SORL1 expression seen in neurons, the glial cells right next to the neurons have normal expression patterns.

How to do this? Y2H IP At various stages of AD progression, and in various environments RNAi Easier than full-fledged KOs (even though KOs might be more interesting to follow) Microarrays to track expression levels temporally Is there a critical period in disease onset? Done across tissues in different conditions to better understand regulation

Thanks Thanks to Ahna and the Genetics 677 class for insightful feedback throughout the semester. Any Questions? Image from Clip Art