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An intestinal sphingolipid promotes neuronal health across generations

Wenyue Wang, Tessa Sherry, Xinran Cheng, Qi Fan, Rebecca Cornell, Jie Liu, Zhicheng Xiao, Roger Pocock

Preprint posted on 24 July 2022 https://www.biorxiv.org/content/10.1101/2022.07.24.501274v1

You are what your mother eats – ursolic acid intake protects progeny from neurodegeneration.

Selected by Chee Kiang Ewe

Background:

With only 302 neurons, the nematode C. elegans provides a highly trackable system to study the molecular mechanisms underlying neurogenesis and neuron degeneration (Alexander et al., 2014). The posterior lateral mechanosensory (PLM) neurons extend axons along the length of the worms to mediate the touch response. It was previously shown that the loss of MEC-17, an α-tubulin acetyltransferase, causes PLM axon degeneration. The defects observed after the loss of MEC-17 is enhanced in lon-2(-) mutants which exhibit increased body length (Neumann & Hilliard, 2014). In this exciting preprint, the authors show that feeding the mec-17(-); lon-2(-) double mutant animals with ursolic acid (UA), a natural plant product, leads to a heritable reduction of PLM axon degeneration. This intergenerational effect depends on the biogenesis of sphingosine-1-phosphate (S1P) and intestine-to-oocyte transfer of yolk. Hence, this work reveals that lipid homeostasis impacts neurodegeneration and regulates intergenerational epigenetic inheritance.

Major findings:

  1. UA confers protection against axon degeneration.

In this preprint, the authors observed that treating mec-17(-); lon-2(-) double mutant worms with UA, specifically during reproductive stage, rescued axon degeneration in their progeny. They found that the gene asah-1, which encodes an acid ceramidase that hydrolyzes ceramide into fatty acid and sphingosine, is strongly upregulated upon UA treatment. They further found that UA failed to prevent axon degeneration in animals lacking asah-1, showing ASAH-1 is required for the neuroprotective effect of UA. Using a transgenic reporter, the authors showed that asah-1 is expressed in the intestine. Overexpressing asah-1 reduced axon degeneration, similar to the effect observed upon UA treatment. Also, overexpressing SPTL-1, a serine palmitoyltransferase required for ceramide biogenesis, or SPHK-1, a sphingosine kinase, in the intestine prevented axon degeneration. On the other hand, the loss of sphk-1 prevented UA-induced neuroprotection. Hence, the authors demonstrated that UA protected against axon degeneration by promoting S1P synthesis in the intestine. Indeed, incubating the mothers with S1P prevented axon degeneration in the progeny.

  1. PQM-1 and CEH-60 activate asah-1 in response to UA exposure.

To identify the upstream regulator(s) of asah-1, the authors examined published ChIP-seq data and found that PQM-1, a GATA zinc finger transcription factor, and CHE-60, a TALE class transcription factor, might bind to asah-1 and control its expression. Indeed, the loss of PQM-1 or CHE-60 abrogated UA-induced upregulation of asah-1. Importantly, animals lacking pqm-1 or che-60 did not respond to UA treatment. These findings suggest that PQM-1 and CHE-60 activate asah-1 in response to UA treatment, leading to the upregulation of S1P biogenesis, which in turn promotes neuroprotection.

  1. Maternal provision of S1P prevents axon degeneration in progeny for two generations.

The authors showed that axon degeneration in the animals was reduced only when their mothers were treated with UA or S1P during the reproduction stage. They found that this intergenerational effect depends on RME-2, a low-density lipoprotein receptor required for the uptake of yolk into the oocytes, suggesting that S1P synthesized in the intestine is imported into the oocytes along with yolk. Strikingly, the authors found that the neuroprotective effect of UA treatment persisted in the F2 progeny, suggesting epigenetic inheritance. Furthermore, the authors showed that exposing the animals to S1P for 16 hours caused upregulation of asah-1 that persists for two generations, providing strong evidence for heritable epigenetic regulation of neuronal health.

Figure 1: A model summarizing how UA might protect against PLM axon degeneration (adapted from Figure 4, Wang W. et al., 2022).

What I liked about this preprint:

This preprint provides a very interesting link between maternal metabolism and neuronal health in the progeny. The authors beautifully demonstrated that yolk is a major carrier of epigenetic information. It is of great interest to understand how physiology and development of animals are shaped by environmental inputs that trigger epigenetic inheritance which may ultimately influence the evolutionary trajectory of the species.

Questions for the authors:

  1. Do you know anything about the turnover rate of S1P? How might maternal S1P contribution exert neuroprotective effect in F1 adults?
  2. Have you considered checking whether S1P causes persistent epigenetic changes (e.g., small RNA pool and/or histone modifications)?

References:

Alexander, A. G., Marfil, V., & Li, C. (2014). Use of C. elegans as a model to study Alzheimer’s disease and other neurodegenerative diseases. Frontiers in Genetics, 5(JUL), 279. https://doi.org/10.3389/FGENE.2014.00279/BIBTEX

Neumann, B., & Hilliard, M. A. (2014). Loss of MEC-17 leads to microtubule instability and axonal degeneration. Cell Reports, 6(1), 93–103. https://doi.org/10.1016/J.CELREP.2013.12.004

 

Tags: axon degeneration, epigenetic inheritance, neurodegeneration

Posted on: 29 August 2022

doi: https://doi.org/10.1242/prelights.32598

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