Sortilin-related receptor and Alzheimers diseaseLuke LopasGenetics 6774/30/09
OverviewIntro to ADSORL1Evidence for SORL1 in ADSemester ResultsThe 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
Between 2.5 and 4.5 million affected Americans
Image from http://www.alz.org/brain/09.asphttp://www.youtube.com/watch?v=76P6Xm3WsEM
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.SORL1Image 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 roleDodson, S.E. et. al. J. Neurosci. 2008;28:12877-12886
Dodson ContinuedDodson, S.E. et. al. J. Neurosci. 2008;28:12877-12886Significant correlation between: 1)Lr11 levels2)amyloid beta levels3)amyloid beta plaque density, and plaque count
SORL1 StatsGene Accession #: NC_000011.8Total Base Pairs: 177,492Total AA: 2,214Location: 11q23.2-q24.2
Limited by most programs only accepting 60,000 base pairs.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 OntologyBiological Process: receptor-mediated endocytosisCellular Component: integral to plasma membraneMolecular Function: low-density lipoprotein binding and transmembrane receptor activity.Image from the Gene Ontology
Protein DomainsDomains: VPS10, LY, EGF, Ldla, FN3Images retrieved from SMART. Schultz et al. (1998) Proc. Natl. Acad. Sci. USA 95, 5857-5864HumanMouse
Homology and PhylogenyImage from TreeDynImage from TreeTop
Going forwardWe 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
How to do this?Y2HIPAt various stages of AD progression, and in various environmentsRNAiEasier than full-fledged KOs (even though KOs might be more interesting to follow)Microarrays to track expression levels temporallyIs there a critical period in disease onset?Done across tissues in different conditions to better understand regulation
ThanksThanks to Ahna and the Genetics 677 class for insightful feedback throughout the semester.
Any Questions?Image from Clip Art
***Movie: What strikes me? How young the people were, and how he didnt 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****Limited and frustrated by DNA searching technology as that is where most of the keys lie and couldnt 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.**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*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.*Specifically, while there is a degrease in SORL1 expression seen in neurons, the glial cells right next to the neurons have normal expression patterns.**