Neuronal regulation of proteostasis; a new target for the development of neurodegeneration therapies

Cells have evolved a nexus of mechanisms that maintain the integrity of the proteome. These mechanisms, which are known as “the proteostasis network (PN)”, assist protein folding, supervise the integrity of mature proteins and direct damaged polypeptides for degradation. Nevertheless, as the organism ages, aggregation-prone proteins challenge the PN and form insoluble aggregates that in some cases underlie the development of late-onset disorders such as Alzheimer ’s disease (AD) and Huntington’s disease (HD). How proteostasis is regulated at the organismal level and whether the PN differentially responds to dissimilar challenges are largely unanswered questions. Employing model nematodes that express neurodegeneration-linked aggregative proteins, we identified a neuronal receptor that controls proteostasis in remote tissues. Searching for coordinators of proteostasis, we discovered that Torsin chaperones (Torsin 1 and 2) which protect model worms from the aggregation of the HD-causing, abnormally long poly-glutamine (polyQ) stretches, expose nematodes to the toxicity of the AD-causing peptide, Aβ. To test how these responses are regulated we compared the transcriptomes of worms that express Aβ to these of their counterparts which express polyQ, asking which genes respond in opposing manners in the two worm strains. We found that a subset of neuropeptides are upregulated in polyQ-expressing worms and downregulated in Aβ-expressing nematodes. These neuropeptides serve as neuron-to-soma proteostasis-controlling messengers. In sum we show that neurons regulate proteostasis across the organism and highlight the importance of understanding the accurate organismal response to the toxicity of specific aggregative proteins to design specifically tailored therapies.