A few weeks ago, Vivian wrote a post about prion disease, discussing how understanding the mechanisms of Kuru could help us design treatments for other neurodegenerative disorders characterized by protein aggregations. The accumulation of protein as a pathological process has also been investigted outside the brain. Aging and degeneration are complex system-wide phenomena and studies like the one by Demontis and Perrimon (2011) show that by looking outside the brain we can unveil new whole-body regulatory mechanisms for neurodegeneration. Demontis and Perrimon (2011) looked at aging-induced protein aggregates in Drosophila muscle that lead to loss of muscle function. The authors show that the transcription factor FoxO, together with its target 4E-BP, is a key element in removing damaged proteins by promoting autophagy and lysosomal action. FoxO had previously been implicated in the mediation of aging as a downstream target of insulin. The authors show that an overexpression of exogenous FoxO in muscle leads to a complete ‘cleaning’ of the tissue from protein aggregates, and a knock-out to an excessive accumulation. They also show that a ‘cleaner’ tissue is more resistant to aging-related decay, while a tissue with high protein aggregation (following FoxO knock-out, or overexpression of aggregation-prone mutated proteins) is associated with a decrease in lifespan.
This is a rather beautiful mechanism in and of itself, but Demontis and Perrimon go on to show that an overexpression of FoxO in muscle tissue, can lead to a decrease in protein aggregation all over the body, particularly in the retina, brain and adipose tissue (see cover figure). They suggest that FoxO-rich muscle can protect the whole body from aging through the protective mechanisms associated with decreased food intake. An inhibition of feeding behaviour and reduced insulin production can enhance 4E-BP at an organism-wide level, thereby promoting systemic proteostasis. This indicates new ways in which healthy muscle tissue affects our brain, and bodies. It also suggests a stronger link between neurodegenerative disorders and the aging of our bodies than we may have imagined.
Demontis F, Perrimon N (2011) FOXO/4E-BP signaling in Drosophila muscle regulates organism-wide proteostasis during aging, Cell, 143(5).