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SMN deficiency perturbs monoamine neurotransmitter metabolism in spinal muscular atrophy
Beyond motor neuron degeneration, homozygous mutations in the survival motor neuron 1 (SMN1) gene cause multiorgan and metabolic defects in patients with spinal muscular atrophy (SMA). However, the precise biochemical features of these alterations and the age of onset in the brain and peripheral org...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10643621/ https://www.ncbi.nlm.nih.gov/pubmed/37957344 http://dx.doi.org/10.1038/s42003-023-05543-1 |
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author | Valsecchi, Valeria Errico, Francesco Bassareo, Valentina Marino, Carmen Nuzzo, Tommaso Brancaccio, Paola Laudati, Giusy Casamassa, Antonella Grimaldi, Manuela D’Amico, Adele Carta, Manolo Bertini, Enrico Pignataro, Giuseppe D’Ursi, Anna Maria Usiello, Alessandro |
author_facet | Valsecchi, Valeria Errico, Francesco Bassareo, Valentina Marino, Carmen Nuzzo, Tommaso Brancaccio, Paola Laudati, Giusy Casamassa, Antonella Grimaldi, Manuela D’Amico, Adele Carta, Manolo Bertini, Enrico Pignataro, Giuseppe D’Ursi, Anna Maria Usiello, Alessandro |
author_sort | Valsecchi, Valeria |
collection | PubMed |
description | Beyond motor neuron degeneration, homozygous mutations in the survival motor neuron 1 (SMN1) gene cause multiorgan and metabolic defects in patients with spinal muscular atrophy (SMA). However, the precise biochemical features of these alterations and the age of onset in the brain and peripheral organs remain unclear. Using untargeted NMR-based metabolomics in SMA mice, we identify cerebral and hepatic abnormalities related to energy homeostasis pathways and amino acid metabolism, emerging already at postnatal day 3 (P3) in the liver. Through HPLC, we find that SMN deficiency induces a drop in cerebral norepinephrine levels in overt symptomatic SMA mice at P11, affecting the mRNA and protein expression of key genes regulating monoamine metabolism, including aromatic L-amino acid decarboxylase (AADC), dopamine beta-hydroxylase (DβH) and monoamine oxidase A (MAO-A). In support of the translational value of our preclinical observations, we also discovered that SMN upregulation increases cerebrospinal fluid norepinephrine concentration in Nusinersen-treated SMA1 patients. Our findings highlight a previously unrecognized harmful influence of low SMN levels on the expression of critical enzymes involved in monoamine metabolism, suggesting that SMN-inducing therapies may modulate catecholamine neurotransmission. These results may also be relevant for setting therapeutic approaches to counteract peripheral metabolic defects in SMA. |
format | Online Article Text |
id | pubmed-10643621 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-106436212023-11-13 SMN deficiency perturbs monoamine neurotransmitter metabolism in spinal muscular atrophy Valsecchi, Valeria Errico, Francesco Bassareo, Valentina Marino, Carmen Nuzzo, Tommaso Brancaccio, Paola Laudati, Giusy Casamassa, Antonella Grimaldi, Manuela D’Amico, Adele Carta, Manolo Bertini, Enrico Pignataro, Giuseppe D’Ursi, Anna Maria Usiello, Alessandro Commun Biol Article Beyond motor neuron degeneration, homozygous mutations in the survival motor neuron 1 (SMN1) gene cause multiorgan and metabolic defects in patients with spinal muscular atrophy (SMA). However, the precise biochemical features of these alterations and the age of onset in the brain and peripheral organs remain unclear. Using untargeted NMR-based metabolomics in SMA mice, we identify cerebral and hepatic abnormalities related to energy homeostasis pathways and amino acid metabolism, emerging already at postnatal day 3 (P3) in the liver. Through HPLC, we find that SMN deficiency induces a drop in cerebral norepinephrine levels in overt symptomatic SMA mice at P11, affecting the mRNA and protein expression of key genes regulating monoamine metabolism, including aromatic L-amino acid decarboxylase (AADC), dopamine beta-hydroxylase (DβH) and monoamine oxidase A (MAO-A). In support of the translational value of our preclinical observations, we also discovered that SMN upregulation increases cerebrospinal fluid norepinephrine concentration in Nusinersen-treated SMA1 patients. Our findings highlight a previously unrecognized harmful influence of low SMN levels on the expression of critical enzymes involved in monoamine metabolism, suggesting that SMN-inducing therapies may modulate catecholamine neurotransmission. These results may also be relevant for setting therapeutic approaches to counteract peripheral metabolic defects in SMA. Nature Publishing Group UK 2023-11-13 /pmc/articles/PMC10643621/ /pubmed/37957344 http://dx.doi.org/10.1038/s42003-023-05543-1 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Valsecchi, Valeria Errico, Francesco Bassareo, Valentina Marino, Carmen Nuzzo, Tommaso Brancaccio, Paola Laudati, Giusy Casamassa, Antonella Grimaldi, Manuela D’Amico, Adele Carta, Manolo Bertini, Enrico Pignataro, Giuseppe D’Ursi, Anna Maria Usiello, Alessandro SMN deficiency perturbs monoamine neurotransmitter metabolism in spinal muscular atrophy |
title | SMN deficiency perturbs monoamine neurotransmitter metabolism in spinal muscular atrophy |
title_full | SMN deficiency perturbs monoamine neurotransmitter metabolism in spinal muscular atrophy |
title_fullStr | SMN deficiency perturbs monoamine neurotransmitter metabolism in spinal muscular atrophy |
title_full_unstemmed | SMN deficiency perturbs monoamine neurotransmitter metabolism in spinal muscular atrophy |
title_short | SMN deficiency perturbs monoamine neurotransmitter metabolism in spinal muscular atrophy |
title_sort | smn deficiency perturbs monoamine neurotransmitter metabolism in spinal muscular atrophy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10643621/ https://www.ncbi.nlm.nih.gov/pubmed/37957344 http://dx.doi.org/10.1038/s42003-023-05543-1 |
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