A comprehensive spatiotemporal map of dystrophin isoform expression in the developing and adult human brain
Abstract Mutations in the dystrophin gene (DMD) cause the severe muscle-wasting disease Duchenne muscular dystrophy (DMD). Additionally, there is a high incidence of intellectual disability and neurobehavioural comorbidities in individuals with DMD. Similar behavioural abnormalities are found in mdx...
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BMC
2025-05-01
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| Series: | Acta Neuropathologica Communications |
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| Online Access: | https://doi.org/10.1186/s40478-025-01996-z |
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| author | Francesco Catapano Reem Alkharji Darren Chambers Simran Singh Artadokht Aghaeipour Jyoti Malhotra Patrizia Ferretti Rahul Phadke Francesco Muntoni |
| author_facet | Francesco Catapano Reem Alkharji Darren Chambers Simran Singh Artadokht Aghaeipour Jyoti Malhotra Patrizia Ferretti Rahul Phadke Francesco Muntoni |
| author_sort | Francesco Catapano |
| collection | DOAJ |
| description | Abstract Mutations in the dystrophin gene (DMD) cause the severe muscle-wasting disease Duchenne muscular dystrophy (DMD). Additionally, there is a high incidence of intellectual disability and neurobehavioural comorbidities in individuals with DMD. Similar behavioural abnormalities are found in mdx dystrophic mouse models. Unlike muscle, several dystrophin isoforms are expressed in the human brain, but a detailed map of regional and cellular localisation of dystrophin isoforms is missing. This is crucial in understanding the neuropathology of DMD individuals, and for evaluating the translatability of pre-clinical findings in DMD mouse models receiving genetic therapy interventions. Here, we provide a comprehensive dystrophin expression profile in human brains from early development to adulthood. We reveal expression of dp427p2, dp427c, dp427m and dp40 isoforms in human embryonic brains, not previously reported. We also detected dp427p2 expression and developmental regulation in human brain across the lifespan. In addition we showed by in situ hybridisation that dp140 was greatly downregulated in adult brains. Importantly, our data also demonstrate expression of DMD transcripts in human motor neurons and co-expression of different dystrophin isoforms within single neurons in both developing and adult brains. Finally, we show localisation of DMD transcripts with GAD1+ GABAergic-associated transcripts in neurons including cerebellar Purkinje cells and interneurons, as well as in the majority of neocortical and hippocampal SLC17A7+ glutamatergic neurons, suggesting a role for dystrophin in signalling at the neuronal inhibitory and excitatory synapses. Graphical abstract |
| format | Article |
| id | doaj-art-ac19e6a5e7364b2cbd59e9bd1990d092 |
| institution | OA Journals |
| issn | 2051-5960 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj-art-ac19e6a5e7364b2cbd59e9bd1990d0922025-08-20T02:29:46ZengBMCActa Neuropathologica Communications2051-59602025-05-0113112810.1186/s40478-025-01996-zA comprehensive spatiotemporal map of dystrophin isoform expression in the developing and adult human brainFrancesco Catapano0Reem Alkharji1Darren Chambers2Simran Singh3Artadokht Aghaeipour4Jyoti Malhotra5Patrizia Ferretti6Rahul Phadke7Francesco Muntoni8The Dubowitz Neuromuscular Centre, Developmental Neurosciences Programme, Great Ormond Street Institute of Child Health, University College LondonDevelopmental Biology and Cancer Department, UCL Great Ormond Street Institute of Child HealthThe Dubowitz Neuromuscular Centre, Developmental Neurosciences Programme, Great Ormond Street Institute of Child Health, University College LondonThe Dubowitz Neuromuscular Centre, Developmental Neurosciences Programme, Great Ormond Street Institute of Child Health, University College LondonThe Dubowitz Neuromuscular Centre, Developmental Neurosciences Programme, Great Ormond Street Institute of Child Health, University College LondonSarepta Therapeutics Lnc.Developmental Biology and Cancer Department, UCL Great Ormond Street Institute of Child HealthThe Dubowitz Neuromuscular Centre, Developmental Neurosciences Programme, Great Ormond Street Institute of Child Health, University College LondonThe Dubowitz Neuromuscular Centre, Developmental Neurosciences Programme, Great Ormond Street Institute of Child Health, University College LondonAbstract Mutations in the dystrophin gene (DMD) cause the severe muscle-wasting disease Duchenne muscular dystrophy (DMD). Additionally, there is a high incidence of intellectual disability and neurobehavioural comorbidities in individuals with DMD. Similar behavioural abnormalities are found in mdx dystrophic mouse models. Unlike muscle, several dystrophin isoforms are expressed in the human brain, but a detailed map of regional and cellular localisation of dystrophin isoforms is missing. This is crucial in understanding the neuropathology of DMD individuals, and for evaluating the translatability of pre-clinical findings in DMD mouse models receiving genetic therapy interventions. Here, we provide a comprehensive dystrophin expression profile in human brains from early development to adulthood. We reveal expression of dp427p2, dp427c, dp427m and dp40 isoforms in human embryonic brains, not previously reported. We also detected dp427p2 expression and developmental regulation in human brain across the lifespan. In addition we showed by in situ hybridisation that dp140 was greatly downregulated in adult brains. Importantly, our data also demonstrate expression of DMD transcripts in human motor neurons and co-expression of different dystrophin isoforms within single neurons in both developing and adult brains. Finally, we show localisation of DMD transcripts with GAD1+ GABAergic-associated transcripts in neurons including cerebellar Purkinje cells and interneurons, as well as in the majority of neocortical and hippocampal SLC17A7+ glutamatergic neurons, suggesting a role for dystrophin in signalling at the neuronal inhibitory and excitatory synapses. Graphical abstracthttps://doi.org/10.1186/s40478-025-01996-zDystrophinDuchenne muscular dystrophyIntellectual disabilityHuman brainGABAergic neuronPurkinje neurons |
| spellingShingle | Francesco Catapano Reem Alkharji Darren Chambers Simran Singh Artadokht Aghaeipour Jyoti Malhotra Patrizia Ferretti Rahul Phadke Francesco Muntoni A comprehensive spatiotemporal map of dystrophin isoform expression in the developing and adult human brain Acta Neuropathologica Communications Dystrophin Duchenne muscular dystrophy Intellectual disability Human brain GABAergic neuron Purkinje neurons |
| title | A comprehensive spatiotemporal map of dystrophin isoform expression in the developing and adult human brain |
| title_full | A comprehensive spatiotemporal map of dystrophin isoform expression in the developing and adult human brain |
| title_fullStr | A comprehensive spatiotemporal map of dystrophin isoform expression in the developing and adult human brain |
| title_full_unstemmed | A comprehensive spatiotemporal map of dystrophin isoform expression in the developing and adult human brain |
| title_short | A comprehensive spatiotemporal map of dystrophin isoform expression in the developing and adult human brain |
| title_sort | comprehensive spatiotemporal map of dystrophin isoform expression in the developing and adult human brain |
| topic | Dystrophin Duchenne muscular dystrophy Intellectual disability Human brain GABAergic neuron Purkinje neurons |
| url | https://doi.org/10.1186/s40478-025-01996-z |
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