sortilin-related receptor and alzheimer’s disease
DESCRIPTION
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”. - PowerPoint PPT PresentationTRANSCRIPT
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Sortilin-related receptor and Alzheimer’s disease
Luke Lopas
Genetics 677
4/30/09
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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
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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
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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).
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Evidence for this role
Dodson, S.E. et. al. J. Neurosci. 2008;28:12877-12886
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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
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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.
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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
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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
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Homology and Phylogeny
Image from TreeDyn
Image from TreeTop
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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
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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
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Thanks
• Thanks to Ahna and the Genetics 677 class for insightful feedback throughout the semester.
• Any Questions?
Image from Clip Art