A number of age-related human diseases are characterized by the appearance of protein aggregates, including neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s. The latter is an example of an inherited polyglutamine expansion disease, in which the expansion of a trinucleotide repeat encoding glutamine leads to the production of an aggregation-prone protein. In Huntingdon’s disease the age of onset correlates with the length of the polyglutamine (polyQ) expansion in huntingtin protein, but among individuals carrying the same number of repeats there is also considerable variation in age of onset and severity, thought to be largely due to variation in other genes. Such natural genetic modifiers of disease susceptibility should give insight into the genes and networks that can be pharmacologically modified without harm to the organism but have proved difficult to identify from genetic studies in human populations. A study published in BMC Biology by Tali Gidalevitz and Richard Morimoto from Northwestern University, USA, and colleagues, now suggests that wild strains of a simple model organism, the nematode C. elegans can provide some helpful leads.
C. elegans has already proved useful for studying the cellular toxicity caused by polyglutamine and other disease-associated proteins in the fixed genetic background of a laboratory strain, and the new research extends the utility of the model by showing that numerous natural genetic modifiers of polyglutamine disease exist in wild worm populations. Previous work has already identified specific genes and pathways that can be manipulated to modify the phenotype caused by protein destabilizing mutations, but amelioration of disease is often achieved at some other cost to the organism. The study establishes C. elegans as a genetically tractable model for identifying modifiers of protein homeostasis among natural variants shaped by selection for the overall fitness of the organism, and could lead to new therapeutic targets.
A worm which as an adult has only about 1,000 cells overall and 301 neurons may seem an unlikely model for studying human neurodegenerative disease, but the cellular pathways governing protein homeostasis are conserved across eukaryotes, and as Matt Kaeberlein from the University of Washington Medical Center, USA, explains in a commentary accompanying the publication of the research article, C. elegans has several features that have contributed to its utility as a model organism, and key aspects of proteotoxic diseases are recapitulated in transgenic worms expressing aggregation-prone proteins.
In the polyQ disease model used by Gidalavitz and Morimoto (one which was originally developed in the Morimoto lab), a fluorescent-tagged peptide encoding a stretch of 40 glutamines is expressed from a transgene specifically in muscle cells, allowing age-associated aggregation to be monitored in vivo, while assessing toxicity through effects on muscle function and lifespan in the same animals. In the new study, the researchers introduced the transgene (by introgressive breeding) into three wild strains of C. elegans, finding that genetic background affected both the age of onset and extent of aggregation, and also which subsets of muscles cells are most likely to form aggregate. They also observed that modifying effects on aggregation and measures of toxicity did not always correlate, with one wild background providing significant protection against muscle paralysis in body wall and reproductive muscle without suppressing aggregation (compared to the original laboratory strain).
The existence of modifiers that can act independently on the aggregation and toxicity phenotypes was further supported by a series of 21 recombinant inbred lines generated between the laboratory strain and the wild strain that showed the greatest enhancement of aggregation, while the existence of multiple modifiers and interactions between them was indicated by transgression – some of the inbred lines had a more extreme aggregation phenotype than either parental line. Overall the results suggest the existence of different and complex modifying pathways, which will be amenable to further dissection and characterization, and may be amenable to therapeutic manipulation.
Written by Penelope Austin, Associate Editor for BMC Biology.