Enzymes of physiological amyloidogenesis control pathological amyloid toxicity

TL;DR

This study shows that enzymes involved in RNA processing can control the toxicity of amyloid proteins linked to Alzheimer's and Parkinson's diseases.

Contribution

The study reveals that RNA tailing and decay enzymes regulate pathological amyloid toxicity in neurodegenerative disease models.

Findings

TENT4b and TENT2 enzymes reduce β-amyloid and α-synuclein toxicity by forming nontoxic amyloid assemblies.

Exosc10 enhances amyloid toxicity, and its depletion prevents cognitive decline in mouse models.

Physiological amyloidogenesis pathways influence the progression of pathological amyloid diseases.

Abstract

This study finds that modulating RNA tailing and decay enzymes can regulate proteotoxicity in Alzheimer’s and Parkinson’s disease models.

Physiological amyloidogenesis drives the formation of functional amyloids involved in various biochemical pathways. We recently showed that the RNA tailing and decay machinery controls the maturation of intracellular amyloid-like aggregates. This raises the question of whether enzymes that participate in the maturation of physiological amyloids are involved in pathological amyloidogenesis implicated in human proteopathies. Using Caenorhabditis elegans and mouse models of pathological amyloids, we show that manipulating the RNA tailing–decay axis alters the toxicity of β-amyloid and α-synuclein involved in Alzheimer’s and Parkinson’s diseases, respectively. The RNA tailing enzymes TENT4b and TENT2 protect against β-amyloid– and α-synuclein–induced toxicity by facilitating the formation of nontoxic amyloidogenic assemblies. In contrast, the RNA exonuclease Exosc10 potentiates pathological amyloid toxicity. Remarkably, Exosc10 depletion prevents cognitive decline and restores memory in two different mouse models of β-amyloid neurotoxicity. Taken together, these results suggest that pathways of physiological amyloidogenesis participate in pathological amyloid etiology.

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