Abstract
BackgroundMonogenic protein aggregation diseases, in addition to cell selectivity, exhibit clinical variation in the age of onset and progression, driven in part by inter-individual genetic variation. While natural genetic variants may pinpoint plastic networks amenable to intervention, the mechanisms by which they impact individual susceptibility to proteotoxicity are still largely unknown.ResultsWe have previously shown that natural variation modifies polyglutamine (polyQ) aggregation phenotypes in C. elegans muscle cells. Here, we find that a genomic locus from C. elegans wild isolate DR1350 causes two genetically separable aggregation phenotypes, without changing the basal activity of muscle proteostasis pathways known to affect polyQ aggregation. We find that the increased aggregation phenotype was due to regulatory variants in the gene encoding a conserved autophagy protein ATG-5. The atg-5 gene itself conferred dosage-dependent enhancement of aggregation, with the DR1350-derived allele behaving as hypermorph. Surprisingly, increased aggregation in animals carrying the modifier locus was accompanied by enhanced autophagy activation in response to activating treatment. Because autophagy is expected to clear, not increase, protein aggregates, we activated autophagy in three different polyQ models and found a striking tissue-dependent effect: activation of autophagy decreased polyQ aggregation in neurons and intestine, but increased it in the muscle cells.ConclusionsOur data show that cryptic natural variants in genes encoding proteostasis components, although not causing detectable phenotypes in wild-type individuals, can have profound effects on aggregation-prone proteins. Clinical applications of autophagy activators for aggregation diseases may need to consider the unexpected divergent effects of autophagy in different cell types.
Highlights
Monogenic protein aggregation diseases, in addition to cell selectivity, exhibit clinical variation in the age of onset and progression, driven in part by inter-individual genetic variation
DR1350-derived variants increase polyglutamine aggregation We previously found that introgression of an integrated polyglutamine-encoding transgene (Q40) from the laboratory Bristol/N2 background (Q40Bristol) into the wild California isolate DR1350 resulted in strongly accelerated polyglutamine aggregation in the body-wall muscle cells, and a characteristic switch in the relative susceptibility of the normally resistant head muscle cells to polyQ aggregation [38]
The DR1350 parent belongs to the isotype defined by the California-derived strain CB4853
Summary
In addition to cell selectivity, exhibit clinical variation in the age of onset and progression, driven in part by inter-individual genetic variation. The variation is thought to result, in addition to stochastic and environmental factors, from variants present in individual’s genetic background that act as modifiers [11,12,13] These genetic modifiers can affect proteins and regulatory pathways that either interact with the disease-causing mutant proteins, or are themselves impacted in disease [14]. Natural variants may indicate pathways that differ from those found by the traditional approaches such as association studies, mutagenesis, or RNAi screens Because these modifiers are a part of natural genetic variation and are present in phenotypically normal individuals, they may pinpoint therapeutic routes that are less likely to cause detrimental side effects
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