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Human HINT1 Mutant Proteins that Cause Axonal Motor Neuropathy Exhibit Anomalous Interactions with Partner Proteins

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Abstract

The 14 kDa histidine triad nucleotide-binding protein 1 (HINT1) is critical to maintain the normal function of motor neurons. Thus, a series of human HINT1 mutants cause autosomal recessive axonal neuropathy with neuromyotonia. HINT1 establishes a series of regulatory interactions with signaling proteins, some of which are enriched in motor neurons, such as the type 1 sigma receptor or intracellular domain (ICD) of transmembrane teneurin 1, both of which are also implicated in motor disturbances. In a previous study, we reported the capacity of HINT1 to remove the small ubiquitin-like modifier (SUMO) from a series of substrates and the influence of HINT1 mutants on this activity. We now report how human HINT1 mutations affect the interaction of HINT1 with the regulator of its SUMOylase activity, calcium-activated calmodulin, and its substrate SUMO. Moreover, HINT1 mutants exhibited anomalous interactions with G protein coupled receptors, such as the mu-opioid, and with glutamate N-methyl-D-aspartate receptors as well. Additionally, these HINT1 mutants showed impaired associations with transcriptional regulators such as the regulator of G protein signaling Z2 protein and the cleaved N-terminal ICD of teneurin 1. Thus, the altered enzymatic activity of human HINT1 mutants and their anomalous interactions with partner proteins may disrupt signaling pathways essential to the normal function of human motor neurons.

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Acknowledgments

Elsa Cortés-Montero is a recipient of a Fellowship from MECD [FPU 15/02356]. We would like to thank Gabriela de Alba and María José López for their excellent technical assistance. We also appreciate the advice of the Department of Statistics, Center for Informatics at the Spanish Council for Scientific Research (CSIC).

Funding

This work was supported by Plan Nacional I+D+i [grant number RT-2018-093677-B-100].

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  1. Neuropharmacology, Cajal Institute, Department of Translational Neuroscience, CSIC, Madrid, Spain

    Elsa Cortés-Montero, María Rodríguez-Muñoz, Pilar Sánchez-Blázquez & Javier Garzón-Niño

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The JGN, ECM, and MRM designed the research. ECM and JGN wrote the manuscript. JGN and PSB obtained the funding. ECM and MRM performed the experiments and the statistical analysis of data. All authors approved the final manuscript.

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Correspondence to Javier Garzón-Niño.

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Cortés-Montero, E., Rodríguez-Muñoz, M., Sánchez-Blázquez, P. et al. Human HINT1 Mutant Proteins that Cause Axonal Motor Neuropathy Exhibit Anomalous Interactions with Partner Proteins. Mol Neurobiol 58, 1834–1845 (2021). https://doi.org/10.1007/s12035-020-02265-x

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