Microtubule Activity in Dopaminergic Neurons Affects the Pace of Aging in Flies

In an interesting discovery, researchers here note evidence for the behavior of dopamine generating neurons in the fly brain to have an sizable influence on the pace of aging and longevity in this species. This effect on aging appears to depend on microtubule activity in these cells, but the work leaves open the question of how exactly this change to a very specific population of neurons alters life span. Much more is left to accomplish in order to even begin to speculate on relevance to human biochemistry.

Dopaminergic neurons, a critical modulatory system in the brain, are greatly affected by age, but it is unclear whether it can impact the aging process in animals. During the course of studying a putative scaffolding protein, Mask, a novel role was discovered for dopaminergic neurons in regulating longevity and aging in fruit flies. Overexpressing Mask in dopaminergic neurons leads to a ∼40% increase in lifespan in flies. This effect seems to be specific to the dopaminergic neurons, as overexpressing Mask in neither the entire body nor the nervous system (neurons or glial cells) showed significant effects on the lifespan.

Although the dopaminergic system provides essential modulation on various behaviors and physiological functions, flies devoid of dopamine in their brains and worms lacking the rate-limiting enzymes for dopamine synthesis live a normal lifespan. These results suggest that dopamine systems is not required to drive normal aging. Overexpressing Mask in specific dopaminergic neurons possibly induces a gain-of-function cellular effect, which consequently confers a beneficial outcome on aging and longevity.

The lifespan extension induced by Mask-overexpressing is accompanied by sustained adult locomotor and fecundity in the long-lived flies; and other physiological functions in the adult flies include food intake and insulin production in the brain are not consistently altered by overexpressing Mask in either group of dopaminergic neurons. The recent finding that Mask promotes microtubule dynamics in fly larval motor neurons and body wall muscles led to the postulation that altered microtubule dynamics in the Mask-expressing dopaminergic neurons is the key mediator. Overexpressing the Kinesin heavy chain Unc-10427 or knocking down a component of the Dynein/Dynactin complex, p150Glued28 are two interventions that have been previously shown to impact MT dynamics. Overexpressing Unc-104 or moderately reducing p150Glued level in the same groups of dopaminergic neurons also extend lifespan in flies, thus demonstrating that increasing MT dynamics and reducing microtubule stability in dopaminergic neurons is sufficient to induce lifespan extension in flies.

Link: https://doi.org/10.1101/2020.06.15.153056

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