OYM71: SAD for SORLosers

On Your Mind Neuroscience Podcast

This week on the On Your Mind neuroscience podcast:

Another week has gone by, and Kat and Liam are back to catch up over some science. Liam’s got the proof of his review back from the journal and is reveling in seeing his (many) months of work in a formatted pdf. Meanwhile, Kat’s been plugging away at processing her samples and is unreasonably enraged by a minor setback. When she went to put her samples in an overnight incubation, she discovered that the oven was already in use, and she suddenly identified with an article that she read weeks ago, “How to P*ss off a Scientist”. Liam’s had his own burst of frustration this week when he read the title of a press release that claimed that the differences between the autistic brain and the healthy brain have been identified “for the first time”.

Venting aside, he’s concerned about the implications of misleading titles and has read an article on “scienceyness” which argues that the effects are detrimental. Scienceyness is a take on “truthiness” that describes the phenomenon of people re-sharing overhyped science headlines without knowing/evaluating whether they are true or not. The author of this article suggests that the only outcome of scienceyness is long-term mistrust in science and the related damage to scientists; but Liam’s got a more optimistic view.

And speaking of reading articles with through an optimistic lens, Kat’s read an article in Scientific American, which has a cringe-worthy set-up that’s clearly meant to attract the attention of the public, but has an interesting thesis. The article covers a study that compared massive schizophrenia GWAS data to regions of the genome that have undergone accelerated change during human evolution. The extensive overlap is used as evidence to suggest that there’s an evolutionary genetics explanation why schizophrenia is a uniquely human condition. Then it’s onto this week’s article…

The Paper

Our article this week is published in Cell Stem Cell and uses induced pluripotent stem cells from patients with Sporadic Alzheimer’s Disease (SAD) to discover a unique interaction between SORL1 genotype and cellular phenotypes. The authors chose to study SORL1 because it is a protein that is involved in the cleavage of APP and a gene that has been associated with SAD in previous studies. Using their relatively large number of cell lines from patients and controls, they found no overall difference in SORL1 expression in fibroblasts, neural stem cells, nor in cultured neurons. What’s more, the presence of a protective (P) or risk (R) haplotype at the 5’ end of the SORL1 gene had no impact on SORL1 expression. Importantly, the authors realized that the addition of BDNF and cAMP to their cell medium could impact SORL1 expression so, instead of accepting their negative results as the end of the story, they did follow-up experiments with and without these molecules.

Adding cAMP to the media induced SORL1 expression in all the cell lines, while adding BDNF increased SORL1 expression only in cell lines with the P haplotype. Their genotype-specific findings extend to amyloid beta protein levels, where increased SORL1 decreases the toxic protein only in cell lines with the P haplotype. What’s most interesting about these findings is the lack of segregation between patient and control lines. There are patient lines that do not carry the risk genotype, that must carry risk alleles at other loci, and there are lines that are homozygous for the risk allele, but lack the SAD diagnosis. It is a beautiful example of the genetic complexity of polygenic disorders like SAD, and the potential of iPSCs to study them.

Young J., Daniel A. Williams, Grace Woodruff, Floyd Buen, Arra C. Revilla, Cheryl Herrera, Mason A. Israel, Shauna H. Yuan, Steven D. Edland & Lawrence S.B. Goldstein & (2015). Elucidating Molecular Phenotypes Caused by the SORL1 Alzheimer’s Disease Genetic Risk Factor Using Human Induced Pluripotent Stem Cells, Cell Stem Cell, DOI: http://dx.doi.org/10.1016/j.stem.2015.02.004