April 15, 2022
In a recent issue of EMBO Molecular Medicine, an intriguing study with potential implications for Alzheimer’s disease (AD) by Ring et al. used yeast to look at why human amyloid beta 42 (Abeta42) kills cells. Upon overexpression in yeast, human Abeta42 protein oligomerizes into aggregates that translocate to mitochondria, where the aggregates cause oxidative stress and eventual necrotic-like cell death. Functional mitochondria are required for this Abeta42-mediated death, and a combined genetic and proteomic approach in yeast identified the HSP40-type chaperone Ydj1p as critical for stabilizing the oligomers and escorting them to mitochondria.
The effect of ydj1Δ deletion was to lower toxicity, with the effect specific to Abeta42 and not to a different type of induced cell death in a yeast model for Parkinson’s disease. Further, Ydj1p protein directly interacted with Abeta42 in a co-immunoprecipitation experiment.
Yeast YDJ1 is homologous to human DnaJA1, which, when expressed in yeast, re-established the toxicity of Abeta42 to a ydj1Δ strain, indicating functional complementation. The human protein directly interacted with Abeta42 in a murine model for Alzheimer’s disease and also displayed dysregulation in post mortem brain samples of AD patients.
In a fly model for AD, deletion of Droj2 (the Drosophila melanogaster ortholog of YDJ1 and DnaJA1) not only reduced the toxicity of Abeta42 but significantly improved the short-term olfactory memory loss associated with Abeta42 expression. Together, the authors convincingly demonstrate the strong evolutionary conservation of this particular chaperone and its effects on exacerbating Abeta42-mediated toxicity, cell death, and memory loss in relevant model systems. The use of yeast to identify this key factor indicates the power of a simplified and tractable system and will hopefully lead to progress in treating a terrible disease.
Categories: Research Spotlight
January 04, 2012
Even though it doesn’t have a brain, yeast is teaching us a lot about Alzheimer’s. Researchers are using this simple eukaryote to figure out what previously identified Alzheimer’s-related genes may be doing in humans as well as to identify new genes that might be involved in this terrible disease. Studies like this may even one day help scientists find better treatments.
Alzheimer’s is a form of dementia that hits about 50% of people over 85. The video below has a great summary of the how the disease progresses:
As the video states, plaques and tangles are linked to the memory loss that is associated with Alzheimer’s. Scientists know that the plaques are amyloids of misfolded AΒ peptides and that AΒ peptides that come from the amyloid precursor protein (APP). What they don’t know is how AΒ peptides cause their damage and if it can be stopped. And so far, genome wide association studies (GWAS) in humans have not shed much light on this problem either.
That isn’t to say that GWAS have been a waste of time. They haven’t. These studies have identified a number of alleles of a few genes that impact a person’s risk for ending up with Alzheimer’s. They just haven’t been able to link the build up of plaques with the identified genes. This is where yeast comes in.
Treusch and coworkers created a strain of yeast in which the AΒ peptide was sent to the endoplasmic reticulum. This mimics what happens to the peptide in the cells of Alzheimer’s patients. These yeast grew more slowly and developed protein complexes reminiscent of plaques.
They then added each of 5532 yeast open reading frames to this strain to identify genes that specifically affected its growth rate. Of the 40 different yeast genes they found, two (YAP1802 and INP52) were yeast homologs of human genes (PICALM and SYNJ1) that had already been identified to be important in Alzheimer’s risks. These results validated the screen and gave the researchers the confidence to dive deeper into their results.
The researchers decided to focus on the 12 genes that had very close human homologs. Of these 12 genes, 10 dealt with endocytosis and the cytoskeleton and at least three had been implicated in previous genome wide association studies in humans. Further work by these authors validated four of these genes by showing that they had similar effects on AΒ cell toxicity in the worm model C. elegans.
In one of the most interesting parts of the study, the researchers used the yeast strain to show why the GWAS-identified gene PICALM affects Alzheimer’s patients. Rather than modifying APP trafficking as had been previously proposed, their results support a model where PICALM lessens the impact of misfolded AΒ plaques on the cell.
This study is another example of the awesome power of yeast genetics. Who would have thought that a brainless yeast could teach us so much about Alzheimer’s?
by D. Barry Starr, Ph.D., Director of Outreach Activities, Stanford Genetics