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Neurodegenerative diseases: Lessons from genome-wide screens in small model organisms.

ABSTRACT: Various age-related neurodegenerative diseases, including Parkinson's disease, polyglutamine expansion diseases and Alzheimer's disease, are associated with the accumulation of misfolded proteins in aggregates in the brain. How and why these proteins form aggregates and cause disease is still poorly understood. Small model organisms--the baker's yeast Saccharomyces cerevisiae, the nematode worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster--have been used to model these diseases and high-throughput genetic screens using these models have led to the identification of a large number of genes that modify aggregation and toxicity of the disease proteins. In this review, we revisit these models and provide a comprehensive comparison of the genetic screens performed so far. Our integrative analysis highlights alterations of a wide variety of basic cellular processes. Not all disease proteins are influenced by alterations in the same cellular processes and despite the unifying theme of protein misfolding and aggregation, the pathology of each of the age-related misfolding disorders can be induced or influenced by a disease-protein-specific subset of molecular processes.

SUBMITTER: van Ham TJ

PROVIDER: S-EPMC3378155 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Neurodegenerative diseases: Lessons from genome-wide screens in small model organisms.

van Ham Tjakko J TJ Breitling Rainer R Swertz Morris A MA Nollen Ellen A A EA

EMBO molecular medicine 20091101 8-9

Various age-related neurodegenerative diseases, including Parkinson's disease, polyglutamine expansion diseases and Alzheimer's disease, are associated with the accumulation of misfolded proteins in aggregates in the brain. How and why these proteins form aggregates and cause disease is still poorly understood. Small model organisms--the baker's yeast Saccharomyces cerevisiae, the nematode worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster--have been used to model these diseas ...[more]

PMID: 20049741

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Project description:BackgroundAn array of experimental models have been developed in the small model organisms C. elegans, S. cerevisiae and D. melanogaster for the study of various neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and expanded polyglutamine diseases as exemplified by Huntington's disease (HD) and related ataxias. Genetic approaches to determine the nature of regulators of the disease phenotypes have ranged from small scale to essentially whole genome screens. The published data covers distinct models in all three organisms and one important question is the extent to which shared genetic factors can be uncovered that affect several or all disease models. Surprisingly it has appeared that there may be relatively little overlap and that many of the regulators may be organism or disease-specific. There is, however, a need for a fully integrated analysis of the available genetic data based on careful comparison of orthologues across the species to determine the real extent of overlap.ResultsWe carried out an integrated analysis using C. elegans as the baseline model organism since this is the most widely studied in this context. Combination of data from 28 published studies using small to large scale screens in all three small model organisms gave a total of 950 identifications of genetic regulators. Of these 624 were separate genes with orthologues in C. elegans. In addition, 34 of these genes, which all had human orthologues, were found to overlap across studies. Of the common genetic regulators some such as chaperones, ubiquitin-related enzymes (including the E3 ligase CHIP which directly links the two pathways) and histone deacetylases were involved in expected pathways whereas others such as the peroxisomal acyl CoA-oxidase suggest novel targets for neurodegenerative disease therapyConclusionsWe identified a significant number of overlapping regulators of neurodegenerative disease models. Since the diseases have, as an underlying feature, protein aggregation phenotypes it was not surprising that some of the overlapping genes encode proteins involved in protein folding and protein degradation. Interestingly, however, some of the overlapping genes encode proteins that have not previously featured in targeted studies of neurodegeneration and this information will form a useful resource to be exploited in further studies of potential drug-targets.

Dataset Information

Neurodegenerative diseases: Lessons from genome-wide screens in small model organisms.

Publications

Neurodegenerative diseases: Lessons from genome-wide screens in small model organisms.

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