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Sortilin-related receptor and Alzheimer’s disease

Sortilin-related receptor and Alzheimer’s disease. Luke Lopas Genetics 677 4/30/09. Overview. Intro to AD SORL1 Evidence for SORL1 in AD Semester Results The future - “To boldly go where no man has gone before”.

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Sortilin-related receptor and Alzheimer’s disease

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

  2. Overview • Intro to AD • SORL1 • 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

  3. What is AD? • Most common form of dementia • Neural Degeneration • Progressive • Between 2.5 and 4.5 million affected Americans http://www.youtube.com/watch?v=76P6Xm3WsEM Image from http://www.alz.org/brain/09.asp

  4. 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).

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

  6. 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

  7. 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. 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.

  8. 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

  9. Protein Domains Human Domains: VPS10, LY, EGF, Ldla, FN3 Mouse Images retrieved from SMART. Schultz et al. (1998) Proc. Natl. Acad. Sci. USA95, 5857-5864

  10. Homology and Phylogeny Image from TreeDyn Image from TreeTop

  11. 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

  12. 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

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

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