Neurodegenerative disorders and gut-brain interactions
Alpana Singh, … , Ted M. Dawson, Subhash Kulkarni
Alpana Singh, … , Ted M. Dawson, Subhash Kulkarni
Published July 1, 2021
Citation Information: J Clin Invest. 2021;131(13):e143775. https://doi.org/10.1172/JCI143775.
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Review Series

Neurodegenerative disorders and gut-brain interactions

Abstract

Neurodegenerative disorders (NDs) affect essential functions not only in the CNS, but also cause persistent gut dysfunctions, suggesting that they have an impact on both CNS and gut-innervating neurons. Although the CNS biology of NDs continues to be well studied, how gut-innervating neurons, including those that connect the gut to the brain, are affected by or involved in the etiology of these debilitating and progressive disorders has been understudied. Studies in recent years have shown how CNS and gut biology, aided by the gut-brain connecting neurons, modulate each other’s functions. These studies underscore the importance of exploring the gut-innervating and gut-brain connecting neurons of the CNS and gut function in health, as well as the etiology and progression of dysfunction in NDs. In this Review, we discuss our current understanding of how the various gut-innervating neurons and gut physiology are involved in the etiology of NDs, including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, to cause progressive CNS and persistent gut dysfunction.

Authors

Alpana Singh, Ted M. Dawson, Subhash Kulkarni

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Figure 1

Intra- and extracellular stressors drive NDs.

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Intra- and extracellular stressors drive NDs. Pathological alterations i...
Pathological alterations in normal homeostatic mechanisms of protein genesis, trafficking, and degradation cause the accumulation of misfolded proteins. During the action of normal homeostatic mechanisms, polypeptides are translated outside the nucleus from mRNA transcribed from nuclear DNA and are then folded normally and trafficked to specific locations within the cells. Old proteins are marked for degradation and are trafficked to the lysosome for degradation. In cases of DNA mutations, the translated polypeptides have a higher probability of folding incorrectly, thereby generating degradation-resistant proteins that accumulate to drive pathologies. In addition, intracellular stressors, such as an abundance of ROS generated within cellular mitochondria, or extracellular stressors, such as infections or aberrant proinflammatory cytokine responses to these infections from immune cells, may cause aberrant biogenesis or misfolding of proteins, thus leading to their accumulation. Illustration adapted with permission from Noelle Burgess at the Institute for Cellular Engineering of Johns Hopkins University.