Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the premature death of motor neurons. Serotonin (5-HT) is a crucial neurotransmitter, and its dysfunction, whether as a contributor or by-product, has been implicated in ALS pathogenesis. Here, we summarize current evidence linking serotonergic alterations to ALS, including results from post-mortem and neuroimaging studies, biofluid testing, and studies of ALS animal models. We also discuss the possible role of 5-HT in modulating some important mechanisms of ALS (i.e. glutamate excitotoxity and neuroinflammation) and in regulating ALS phenotypes (i.e. breathing dysfunction and metabolic defects). Finally, we discuss the promise and limitations of the serotonergic system as a target for the development of ALS biomarkers and therapeutic approaches. However, due to a relative paucity of data and standardized methodologies in previous studies, proper interpretation of existing results remains a challenge. Future research is needed to unravel the mechanisms linking serotonergic pathways and ALS and to provide valid, reproducible, and translatable findings.
Graphical Abstract
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Adapted from Sapiensoup (https://sapiensoup.com/serotonin) and Francescangeli et al. (2019), Boyer and Shannon (2005), Pourhamzeh et al. (2021). The drawings are from SMART (https://smart.servier.com/)
Adapted from Karmakar and Lal (2021)
Adapted from Kwon and Koh (2020)
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The authors wish to acknowledge Dr Ning Su, Peking Union Medical College Hospital, for her kind suggestions in manuscript revision.
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This work was supported by grants from the National Natural Science Foundation of China (Grant Number 81750002), the WJP medical foundation (Grant Number 320.6750.17092), CAMS Innovation Fund for Medical Sciences (CIFMS) (Grant Number 2021-I2M-C&T-A-003), and Neuroscience Center of Chinese Academy of Medical Sciences.
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Yang, L., Cheng, Y., Zhu, Y. et al. The Serotonergic System and Amyotrophic Lateral Sclerosis: A Review of Current Evidence. Cell Mol Neurobiol 43, 2387–2414 (2023). https://doi.org/10.1007/s10571-023-01320-0
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DOI: https://doi.org/10.1007/s10571-023-01320-0