Receptor seminar: Associations of SORLA/SORL1 with Alzheimer’s disease


April 26, 2018    
12:00 pm


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Prof. Olav M Andersen, Department of Biomedicine, Aarhus University, Denmark

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Alzheimer’s disease (AD) is the most prevalent form of dementia, but the underlying molecular mechanisms as well as the contribution of associated genetic risk factors are far from understood. I here describe accumulating evidence for SORL1 being an important genetic AD risk factor encoding the neuronal sorting receptor SORLA that shows decreased expression in brain of AD patients.

Using cell and animal models, we have found that SORLA activity protects against Amyloid β-peptide formation by determination of the intraneuronal sorting receptor of the Amyloid precursor protein due in the secretory and endocytic pathways. We have identified cytoplasmic adaptor proteins that regulates SORLA sorting, and found an endocytic/recycling pathway that modify N-glycosylation priming the receptor for ectodomain shedding thus decreasing the intraneuronal bioavailability.

More recently, we have uncovered cis-and trans regulatory mechanisms starting to explain the decrease of SORLA in AD, as well as identified novel SORL1 transcripts that correlate with genetic risk alleles and sheds light on novel receptor functions.

In conclusion, it was recently suggested that pathogenic mutations in the SORL1 gene should be considered next to the pathogenic mutations in PSEN1, PSEN2 and APP, and that SORL1 should be considered as “the fourth” autosomal dominant Alzheimer gene.

Selected publications

Mygind KJ, Störiko T, Freiberg ML, Samsøe-Petersen J, Schwarz J, Andersen OM, Kveiborg M (2018) Sorting nexin 9 (SNX9) regulates levels of the transmembrane disintegrin and metalloproteinase (ADAM)-9 at the cell surface. J Biol Chem. 2018 Apr 5. pii: jbc.RA117.001077. doi: 10.1074/jbc.RA117.001077. [Epub ahead of print]

Dienemann C, Coburger I, Mehmedbasic A, Andersen OM, Than ME (2015) Mutants of metal binding site M1 in APP E2 show metal specific differences in binding of heparin but not of sorLA.  Biochemistry. 2015 Apr 21;54(15):2490-9. doi: 10.1021/acs.biochem.5b00111. Epub 2015 Apr 10.

Mehmedbasic A, Christensen SK, Nilsson J, Rüetschi U, Gustafsen C, Poulsen AS, Rasmussen RW, Fjorback AN, Larson G, Andersen OM (2015) SorLA complement-type repeat domains protect the amyloid precursor protein against processing. J Biol Chem. 2015 Feb 6;290(6):3359-76. doi: 10.1074/jbc.M114.619940. Epub 2014 Dec 18.

Willnow TE, Andersen OM (2013) Sorting receptor SORLA–a trafficking path to avoid Alzheimer disease. J Cell Sci. 2013 Jul 1;126(Pt 13):2751-60. doi: 10.1242/jcs.125393. Epub 2013 Jun 26. Review.

Fjorback AW, Seaman M, Gustafsen C, Mehmedbasic A, Gokool S, Wu C, Militz D, Schmidt V, Madsen P, Nyengaard JR, Willnow TE, Christensen EI, Mobley WB, Nykjær A, Andersen OM (2012) Retromer binds the FANSHY sorting motif in SorLA to regulate amyloid precursor protein sorting and processing. J Neurosci. 2012 Jan 25;32(4):1467-80. doi: 10.1523/JNEUROSCI.2272-11.2012.

Serup Andersen O, Boisguerin P, Glerup S, Skeldal S, Volkmer R, Willnow TE, Nykjaer A, Andersen OM (2010) Identification of a linear epitope in sortilin that partakes in pro-neurotrophin binding. J Biol Chem. 2010 Apr 16;285(16):12210-22. doi: 10.1074/jbc.M109.062364. Epub 2010 Feb 16.

Dodson SE, Andersen OM, Karmali V, Fritz JJ, Cheng D, Peng J, Levey AI, Willnow TE, Lah JJ (2008) Loss of LR11/SORLA enhances early pathology in a mouse model of amyloidosis: evidence for a proximal role in Alzheimer’s disease. J Neurosci. 2008 Nov 26;28(48):12877-86. doi: 10.1523/JNEUROSCI.4582-08.2008