Science is full of mysteries just waiting to be solved. One of these mysteries is the “missing heritability” problem—it turns out that some traits seem hereditary, yet cannot be traced back to nucleic acids or even known epigenetic modifications. Now, a talented team studying C. elegans has spotted protein clumps called amyloids that could be the missing piece of the heritability puzzle.
Amyloids that propagate themselves (e.g. prions) are pathogenic, but some amyloid aggregates of native-state proteins are required for normal functions, such as forming memories and regulating hormones. These clumps were thought to be cleared out early in development, but the team from the lab of W. Brent Derry (University of Toronto, Hospital for Sick Children) put on their Sherlock Holmes caps and saw that some amyloids were inherited in worms. Here’s what they found:
- Deleting genes coding for AN1 zinc finger domain proteins results in less-fertile hermaphrodites in successive generations, and sometimes these worms don’t reproduce
- Mutant hermaphrodite worms can reproduce when crossed to wild-type males
- Double mutant hermaphrodites cannot make sperm, and double mutant males make oocytes instead of sperm
The mutation messes up sex determination, and it appears that the genes encode proteins involved in sperm production and sex determination. The defect is reversible when the temperature changes, so the team called the genes “multigenerational self-sterility and temperature regulated,” or mstr-1 and mstr-2.
In a screen for suppressing mutations that bypass the need of these genes, the team identified regulatory subunits of the proteasome. It was a real “who-dunnit”—the proteasome isn’t known to be involved in defining sex, after all. But they found that the proteasome loses its specificity and degrades proteins that are important for sex determination, such as GLD-1 and TRA-1.
In a grand finale, the caper ends with the team showing that amyloids are responsible for the observations, and that the amyloids are inherited. In a series of experiments, they found:
- Green autofluorescent structures are visible in oocytes in feminized worms at boosted levels compared to wild-type, and the structures persist in embryos, anti-correlating with MSTR-1 expression
- Amyloid dyes stain the structures
- Injecting amyloids from mstr females into wild-type hermaphrodites reduces fertility for at least five generations
- The amyloids also are involved in vulval formation, showing that they could be involved in somatic processes, too.
Overall, MSTR-1 and the proteasome maintain GLD-1 and TRA-1 proteins at the right levels, allowing for proper sex determination, and this is all transmitted through generations by amyloid-like structures.
Grab your magnifying glass and read the details at Nature Cell Biology, September 2024.