The findings may possibly result in a breakthrough in the study of tauopathy, an essetial pathological propety of Alzheimer's disease.

View all comments by Takaomi Saido

These papers report using invertebrate models of human neurodegenerative disease to identify genes that play a role in the cellular toxicity associated with aggregation-prone, disease-relevant proteins. The studies focus on different diseases and use different model organisms, but have the same underlying rationale: use of these models allows “unbiased” screening for relevant genes without any a priori assumptions about the mechanism of disease protein aggregation or toxicity. In the Van Ham et al. study, the nematode worm C. elegans was used to identify genes that influence the aggregation of α-synuclein, believed to play a causal role in Parkinson disease. Cao et al. used transgenic Drosophila expressing the human β amyloid peptide (Aβ), linked to Alzheimer disease, to identify genes that modulate Aβ toxicity. Both studies demonstrate the ability of this approach to uncover unexpected interacting genes, as well as the difficulty of making sense of the genes identified.

The study of Van Ham et al. follows an approach previously used by this...  Read more

These papers report using invertebrate models of human neurodegenerative disease to identify genes that play a role in the cellular toxicity associated with aggregation-prone, disease-relevant proteins. The studies focus on different diseases and use different model organisms, but have the same underlying rationale: use of these models allows “unbiased” screening for relevant genes without any a priori assumptions about the mechanism of disease protein aggregation or toxicity. In the Van Ham et al. study, the nematode worm C. elegans was used to identify genes that influence the aggregation of α-synuclein, believed to play a causal role in Parkinson disease. Cao et al. used transgenic Drosophila expressing the human β amyloid peptide (Aβ), linked to Alzheimer disease, to identify genes that modulate Aβ toxicity. Both studies demonstrate the ability of this approach to uncover unexpected interacting genes, as well as the difficulty of making sense of the genes identified.

The study of Van Ham et al. follows an approach previously used by this group to identify genes involved in the aggregation of a polyglutamine-repeat reporter protein (relevant to polyglutamine-repeat associated diseases such as Huntington’s). Approximately 16,000 C. elegans genes were individually knocked down by RNA interference, and the ability of these gene knockdowns to increase the aggregation of an α-synuclein::GFP fusion reporter protein was assayed. Inhibited expression of 80 genes (~0.5 percent of the total) was found to reproducibly increase the aggregation of the α-synuclein reporter. In my view, the most surprising result is the large range of function of the genes identified, including roles in chemosensation, gene expression, and intracellular protein trafficking. The second most surprising finding is that there is essentially no overlap between genes that influence α-synuclein aggregation and genes that affect polyglutamine-repeat protein aggregation. This result strongly argues that all aggregating proteins are not created equal, at least in the context of this model system. One thing not assayed in this study is a direct measurement of α-synuclein toxicity, so this study cannot address the important question of whether α-synuclein aggregates are directly toxic or represent a defense mechanism against α-synuclein toxicity. The Cao et al. study employs flies expressing (human) β amyloid peptide in their eyes, which leads to visible abnormalities in the fly eye. Using this model, they screened ~2,000 existing mutations for modulation of this abnormal eye phenotype, leading to the identification of 23 mutations (~1 percent of total mutations tested). As in the C. elegans study, the mutated genes have a large range of functions, and do not fall into an obvious single biological pathway (additionally, none of these genes appears to be homologous to the genes identified in the Van Ham study). Unlike the worm study described above, this group found that approximately half of the identified mutations affected the phenotype of model flies expressing a toxic form of huntingtin.

Both of these well-done studies have undertaken extensive, high-throughput screens and identified intriguing collections of genes with potential relevance to Parkinson and Alzheimer disease. What have we learned? Perhaps the most obvious lesson is that much more work will need to be done to sort out what these findings mean and how they can be applied to human disease. Although both studies seek to connect identified genes to the extensive neurodegeneration literature, the importance of these connections is hard to determine. This is due to what I call the “six degrees of separation” problem in biology—the observation that, given the complexity and extensive knowledge base in well-studied biological fields (e.g., neurodegeneration), it is not difficult to make rational connections between even a random list of genes and previously published studies. (This problem hinders interpretation of “hit lists” from gene expression studies in particular.) This skepticism does not weaken the importance of these studies; it just reinforces the notion that there is now some really important biology that needs to be done to understand how the identified genes influence the aggregation or toxicity of disease proteins. In particular, it will be interesting to know which of the modifier genes act cell-autonomously (e.g., the chemotaxis genes identified in the C. elegans study are likely expressed only in neurons—how do they affect α-synuclein aggregation in muscle cells?), and whether identified genes can be ordered in a pathway (e.g., what is the effect of combining a suppressor of Aβ toxicity with an enhancer?). I believe that there is a high probability that some of the genes identified in these studies are telling us important things about neurodegenerative disease—the challenge now is identifying which of these genes are the truly informative ones.

View all comments by Chris Link