Identification of protein aggregates in the aging vertebrate brain with prion-like and phase-separation properties.

Protein aggregation, which can sometimes spread in a prion-like manner, is a hallmark of neurodegenerative diseases. However, whether prion-like aggregates form during normal brain aging remains unknown. Here, we use quantitative proteomics in the African turquoise killifish to identify protein aggregates that accumulate in old vertebrate brains. These aggregates are enriched for prion-like RNA-binding proteins, notably the ATP-dependent RNA helicase DDX5. We validate that DDX5 forms aggregate-like puncta in the brains of old killifish and mice. Interestingly, DDX5's prion-like domain allows these aggregates to propagate across many generations in yeast. In vitro, DDX5 phase separates into condensates. Mutations that abolish DDX5 prion propagation also impair the protein's ability to phase separate. DDX5 condensates exhibit enhanced enzymatic activity, but they can mature into inactive, solid aggregates. Our findings suggest that protein aggregates with prion-like properties form during normal brain aging, which could have implications for the age-dependency of cognitive decline.

Tissue-specific landscape of protein aggregation and quality control in an aging vertebrate.

Protein aggregation is a hallmark of age-related neurodegeneration. Yet, aggregation during normal aging and in tissues other than the brain is poorly understood. Here, we leverage the African turquoise killifish to systematically profile protein aggregates in seven tissues of an aging vertebrate. Age-dependent aggregation is strikingly tissue specific and not simply driven by protein expression differences. Experimental interrogation in killifish and yeast, combined with machine learning, indicates that this specificity is linked to protein-autonomous biophysical features and tissue-selective alterations in protein quality control. Co-aggregation of protein quality control machinery during aging may further reduce proteostasis capacity, exacerbating aggregate burden. A segmental progeria model with accelerated aging in specific tissues exhibits selectively increased aggregation in these same tissues. Intriguingly, many age-related protein aggregates arise in wild-type proteins that, when mutated, drive human diseases. Our data chart a comprehensive landscape of protein aggregation during vertebrate aging and identify strong, tissue-specific associations with dysfunction and disease.

The African Turquoise Killifish Genome Provides Insights into Evolution and Genetic Architecture of Lifespan.

Lifespan is a remarkably diverse trait ranging from a few days to several hundred years in nature, but the mechanisms underlying the evolution of lifespan differences remain elusive. Here we de novo assemble a reference genome for the naturally short-lived African turquoise killifish, providing a unique resource for comparative and experimental genomics. The identification of genes under positive selection in this fish reveals potential candidates to explain its compressed lifespan. Several aging genes are under positive selection in this short-lived fish and long-lived species, raising the intriguing possibility that the same gene could underlie evolution of both compressed and extended lifespans. Comparative genomics and linkage analysis identify candidate genes associated with lifespan differences between various turquoise killifish strains. Remarkably, these genes are clustered on the sex chromosome, suggesting that short lifespan might have co-evolved with sex determination. Our study provides insights into the evolutionary forces that shape lifespan in nature.

Salinity tolerance in diapausing embryos of the annual killifish Austrofundulus limnaeus is supported by exceptionally low water and ion permeability.

The annual killifish Austrofundulus limnaeus inhabits rainwater pools in the Maracaibo basin of Venezuela. This species persists in ephemeral habitats by producing diapausing embryos that are resistant to the stresses imposed by the drying of their aquatic habitat. Embryos of A. limnaeus are likely exposed to a highly variable osmotic environment during development, but their tolerance of osmotic stress has not been characterized. We investigated the capacity of these embryos to survive in hypersaline environments and evaluated the possible mechanisms used to support osmoregulation. Diapausing embryos of A. limnaeus defend their internal osmolality of around 290 mOsmol kg(-1) H(2)O(-1) against salt stress as high as 50 ppt salinity. We find that diapausing embryos of A. limnaeus have a permeability to water that is orders of magnitude lower than other teleost fish embryos. The activity of ion motive ATPases that may be important in the extrusion of ions via mitochondrial rich cells do not appear to be playing a large role in osmoregulation of A. limnaeus embryos. We conclude that for the duration of embryonic development the unique properties of the enveloping cell layer of A. limnaeus embryos acts as a permeability barrier to water and ions and supports osmoregulation in this species in response to a broad range of osmotic environments.