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”

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

Image from http://www.alz.org/brain/09.asp http://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. 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

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

Significant correlation between: 1)Lr11 levels

2)amyloid beta levels

3)amyloid beta plaque density, and plaque count

SORL1 Stats

Gene 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 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

Domains: VPS10, LY, EGF, Ldla, FN3

Images retrieved from SMART. Schultz et al. (1998) Proc. Natl. Acad. Sci. USA 95, 5857-5864

Human

Mouse

Homology and Phylogeny

Image from TreeDyn

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

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