Transcriptional signatures of synaptic vesicle genes define myotonic dystrophy type I neurodegeneration
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- Antonio Jimenez‐Marin
- Computational Neuroimaging Group Biocruces‐Bizkaia Health Research Institute Barakaldo Spain
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- Ibai Diez
- Department of Radiology Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School Boston MA USA
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- Garazi Labayru
- Neuroscience Area Biodonostia Research Institute San Sebastián Spain
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- Andone Sistiaga
- Neuroscience Area Biodonostia Research Institute San Sebastián Spain
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- Maria C. Caballero
- Donostia University Hospital Donostia‐San Sebastian Spain
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- Pol Andres‐Benito
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Institute Carlos III Madrid Spain
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- Jorge Sepulcre
- Department of Radiology Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School Boston MA USA
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- Isidro Ferrer
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Institute Carlos III Madrid Spain
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- Adolfo Lopez de Munain
- Neuroscience Area Biodonostia Research Institute San Sebastián Spain
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- Jesus M. Cortes
- Computational Neuroimaging Group Biocruces‐Bizkaia Health Research Institute Barakaldo Spain
抄録
<jats:title>Abstract</jats:title><jats:sec><jats:title>Aim</jats:title><jats:p>To delineate the neurogenetic profiles of brain degeneration patterns in myotonic dystrophy type I (DM1).</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>In two cohorts of DM1 patients, brain maps of volume loss (VL) and neuropsychological deficits (NDs) were intersected to large‐scale transcriptome maps provided by the Allen Human Brain Atlas (AHBA). For validation, neuropathological and RNA analyses were performed in a small series of DM1 brain samples.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Twofold: (1) From a list of preselected hypothesis‐driven genes, confirmatory analyses found that three genes play a major role in brain degeneration: dystrophin (<jats:italic>DMD)</jats:italic>, alpha‐synuclein (<jats:italic>SNCA)</jats:italic> and the microtubule‐associated protein tau (<jats:italic>MAPT)</jats:italic>. Neuropathological analyses confirmed a highly heterogeneous Tau‐pathology in DM1, different to the one in Alzheimer's disease. (2) Exploratory analyses revealed gene clusters enriched for key biological processes in the central nervous system, such as synaptic vesicle recycling, localization, endocytosis and exocytosis, and the serotonin and dopamine neurotransmitter pathways. RNA analyses confirmed synaptic vesicle dysfunction.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>The combination of large‐scale transcriptome interactions with brain imaging and cognitive function sheds light on the neurobiological mechanisms of brain degeneration in DM1 that might help define future therapeutic strategies and research into this condition.</jats:p></jats:sec>
収録刊行物
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- Neuropathology and Applied Neurobiology
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Neuropathology and Applied Neurobiology 47 (7), 1092-1108, 2021-05-17
Wiley