Investigating the Role of the Sortilins in Alzheimer’s Disease

MRC Institute of Genetics & Molecular Medicine, The University of Edinburgh, UK

The sortilins are a family of five receptors- sortilin, SORL1/SorLA, and SorCS1-3, which are expressed in the developing and mature nervous system, in a region- and cell-type specific manner (1). Through interactions with amyloid precursor protein (APP), neurotrophic and pro-neurotrophic factors, they play an important role in neuronal viability and function (2). Genetic variants in SORL1 have shown significant association with Mendelian and sporadic Alzheimer’s Disease (AD) and further studies have shown that loss of SorLA promotes APP amyloidogenic processing (3). Reduced expression of members of the sortilins is observed in AD and is associated with elevated Aβ (4). In mice, increased Aβ levels are associated with increased DNA double-strand break (DSB) formation and DNA repair deficits following exploration of a novel environment (5).

My project focuses on SorLA and SorCS2 and the cellular consequences of their perturbed function. I am addressing this through studying samples from knock-our mouse models for these genes, as well as by using CRISPR/Cas9 to introduce mutations in SORL1 and SORCS2 in a human neuronal cell line.

DSB formation and repair have been assessed in the dentate gyrus and the CA region of the hippocampus in Sorla and Sorcs2 knock-out mice subjected to a novel environment task. Cell lines deficient for SORL1 and SORCS2 or carrying AD-associated mutations in SORL1 have been generated. The phenotype of the cell lines is currently being examined using DNA sequencing, qRT-PCR and western blotting. In the future, these lines with be used to determine the effect of perturbed SORL1 and SORCS2 function on neuronal morphology (e.g. spine size, synapse number, dendrite morphology and density) and function (e.g. protein trafficking and APP processing). These will be assessed using high content imaging platforms, as well immunocytochemistry and confocal microscopy.

References

1. Glerup S, Nykjaer A and Vaeger CB (2014) Sortilins in Neurotrophic Factor Signalling.  Neurotrophic Factors, Handbook of Experimental Pharmacology 220: 103-119.
2. Nikjaer A and Willnow TE (2012) Sortilin: a receptor to regulate neuronal viability and function. Trends in Neurosciences 35: 261-270.
3. Reitz C et al. (2011) Meta-analysis of the association between variants in SORL1 and Alzheimer disease. Archives of Neurology 68: 99–106.
4. Reitz C et al. (2013) Independent and epistatic effects of variants in VPS10-d receptors on Alzheimer disease risk and processing of the amyloid precurson protein (APP). Translational Psychiatry 3 e256
5. Suberbielle E et al. (2013) Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-β. Nature Neuroscience 16: 613-621.

Funded by:

* entered into the PhD student poster competition