Pulling apart proteotoxicity

Insulin-like growth factor (IGF) signaling plays a prominent role in the genetic determination of lifespan, in organisms ranging in size and complexity from C. elegans to M. musculus.

Some very recent results suggest that IGF signaling also functions in determining the rate and nature of protein aggregation in neurodegenerative diseases such as Alzheimer’s. From Cohen et al., a collaboration between the Dillin lab at the Salk and the Kelly lab at Scripps:

Aberrant protein aggregation is a common feature of late-onset neurodegenerative diseases, including Alzheimer disease (AD) which is associated with the misassembly of the Aß1-42 peptide. Aggregation-mediated Aß1-42 toxicity was reduced in C. elegans when aging was slowed by decreased insulin/insulin growth factor (IGF)-1-like signaling (IIS). The downstream transcription factors, heat shock factor-1 (HSF-1) and DAF-16 regulate opposing disaggregation and aggregation activities to promote cellular survival in response to constitutive toxic protein aggregation. Because the IIS pathway is central to the regulation of longevity and youthfulness in worms, flies and mammals, these results suggest a mechanistic link between the aging process and aggregation-mediated proteotoxicity.

For what comes next, here’s a quick review of IGF signaling and lifespan in the worm: Loss-of-function mutants in DAF-2 (homolog of IGF-1 receptor) are long-lived. HSF-1 (heat shock factor) and DAF-16 (Forkhead/FOXO) encode downstream transcription factors necessary but not sufficient for daf-2 life extension.

The first result described in the abstract bears on the question of why protein aggregation diseases are age-related. Is it because it simply takes a while for aggregates to form and grow, or rather because age-related changes increase the toxicity of the aggregates that form? The delay in proteotoxicity observed in daf-2 worms, which age more slowly than wildtype, argues for the latter interpretation.

The second result in the abstract, along with some painstaking tour de force biochemistry described in the body of the paper, addresses the nature of proteotoxicity itself. Both daf-16 and hsf-1 worms exhibit increased proteotoxicity. The two knockdowns, however, have opposite biochemical effects on Aß aggregation: hsf-1 has higher levels of high-molecular weight aggregates than daf-2, whereas the aggregates are barely detectable in daf-16. Thus, levels of large aggregates correlates poorly with proteotoxicity.

In contrast, the level of small Aß oligomers (on the order of trimers) matches up nicely: daf-2 had the lowest levels, and daf-16 and hsf-1 the highest levels, of both accumulated small oligomers and toxic effects. This forces us to reconsider the role of large protein aggregates, long considered not just a smoking gun but the bullet itself, in Alzheimer’s and other diseases. In the words of senior author Andrew Dillin:

“This second finding is clearly a shift in paradigm. … For nearly a year in this work, we assumed that large aggregates were the toxic species; however, our data proved otherwise. These results further support a shift in thinking for this field regarding the toxicity of small aggregates and lays the framework for new avenues to combat age-onset protein aggregation diseases, such as AD, Parkinson’s, Huntington’s, and ALS owing to the protective biological activities discovered.”

How can we reconcile the curious opposing effects of daf-16 and hsf-1? The authors argue that the two downstream transcription factors have opposing but complementary effects on Aß: HSF-1’s transcriptome drives disaggregation, tightly coupled with degradation. When this preferred pathway is saturated, however, DAF-16’s target genes promote protective aggregation of small Aß oligomers (toxic) into high-molecular weight species (less toxic), which serve as a relatively safe repository for the unwanted protein until such time as the disaggregation machinery can clear it from the cell.


One comment

  1. I don’t know, muscle cells are not neurons, and they have different mechanisms to respond to protein accumulation and turnover, this is especially clear in worms.

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