Haloperidol induces neuroprotection and enhances neuromuscular function in both murine and human models of spinal muscular atrophy.

Overview

1. Department of Neuroscience “Rita Levi Montalcini”, University of Turin,Turin, Italy
2. Neuroscience Institute Cavalieri Ottolenghi, Orbassano,Turin, Italy
3. Human Translational Genomics Group, University Institute of Biotechnology and Biomedicine, Universidad de Valencia,Burjassot, Spain
4. Incliva Biomedical Research Institute,Valencia, Spain
5. INSERM/UEVE, UMR 861, Université Paris Saclay, CECS/I-STEM, AFM-Telethon, Rue Henri Desbruères, Corbeil-Essonnes, France
6. Centre for Biomedical Network Research on Rare Diseases (CIBERER), CB23/07/00005, Carlos III Health Institute,Madrid, Spain
7. Experimental and Applied Biomedicine Research Group, Health Sciences Faculty, Universidad Particular Internacional SEK (UISEK), Quito, Ecuador

Abstract

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by Survival Motor Neuron 1 (SMN1) gene mutations, leading to reduced SMN protein levels and progressive motor neuron (MN) degeneration. Although current therapies aim to restore SMN expression, limitations highlight the need for alternative strategies. We investigated haloperidol (HALO), a classical antipsychotic, as a potential therapeutic based on its ability to enhance SMN2 splicing and SMN expression. Using the delta 7 SMA mouse model, we assessed effects of HALO on survival, motor function, neuroprotection, and neuroinflammation, by histological, molecular, and RNA-sequencing analyses of spinal cord and muscle samples. Additionally, we examined patient induced pluripotent stem cell-derived MNs and myotube co-cultures for validation in human cells. HALO increased lifespan and motor performance in mice with SMA, upregulated SMN protein in spinal cord and muscles, reduced MN loss, and attenuated neuroinflammation. Moreover, HALO enhanced neuromuscular junction integrity and muscle trophism, suggesting peripheral benefits. RNA-sequencing analysis revealed extensive splicing changes, including SMN target transcripts, supporting enhanced activity. In human models, HALO improved MN survival and SMN expression, supporting dual SMN-dependent and neuroprotective mechanisms. Given its central nervous system penetrance and clinical approval, HALO emerges as a promising SMA therapy candidate, warranting further dose optimization and validation for translational potential.

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Data

Datasets cited

• bioproject:PRJNA1251322, at NCBI BioProject; found in “Data availability”

Data availability

All data are available in the main text or Supplementary material. Supplementary Data files 1 and 2 provide complete RNA-seq quantification in spinal cord and quadriceps of treated delta 7 mice, respectively. The RNA-seq datasets generated during this study are publicly available in the NCBI BioProject repository under accession number PRJNA1251322 (https://www.ncbi.nlm.nih.gov/bioproject/?term=PRJNA1251322).

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Version 1, 29 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 5 keywords, 12 MeSH terms, 2 funders, 65 references.

Cite

This paper

Menduti, G., Perez-Gomez, R., Berenger-Currias, N., Ruatti, C., Espinosa-Espinosa, J., Januel, C., Konieczny, P., Artero, R., Martinat, C., & Boido, M. (2026). Haloperidol induces neuroprotection and enhances neuromuscular function in both murine and human models of spinal muscular atrophy. Experimental & molecular medicine, 58(4), 1216-1229. https://doi.org/10.1038/s12276-026-01689-0

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