Central synaptopathy is the most conserved feature of motor circuit pathology across spinal muscular atrophy mouse models
| Autor: | Brunhilde Wirth, Katharina S. Apel, Leonie Sowoidnich, Beatriz Blanco-Redondo, Josiane K. Sime Longang, Florian Gerstner, Jannik M. Buettner, Eva Janzen, Tobias Langenhan, Christian M. Simon |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Pathology
medicine.medical_specialty Multidisciplinary Molecular biology Science Degeneration (medical) Spinal muscular atrophy Disease Molecular neuroscience Motor neuron Biology medicine.disease SMA Article medicine.anatomical_structure nervous system medicine Excitatory postsynaptic potential Synaptopathy Neuroscience |
| Zdroj: | iScience iScience, Vol 24, Iss 11, Pp 103376-(2021) |
| ISSN: | 2589-0042 |
| Popis: | Summary Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by reduced survival motor neuron (SMN) protein. Recently, SMN dysfunction has been linked to individual aspects of motor circuit pathology in a severe SMA mouse model. To determine whether these disease mechanisms are conserved, we directly compared the motor circuit pathology of three SMA mouse models. The severe SMNΔ7 model exhibits vast motor circuit defects, including degeneration of motor neurons, spinal excitatory synapses, and neuromuscular junctions (NMJs). In contrast, the Taiwanese model shows very mild motor neuron pathology, but early central synaptic loss. In the intermediate Smn2B/- model, strong pathology of central excitatory synapses and NMJs precedes the late onset of p53-dependent motor neuron death. These pathological events correlate with SMN-dependent splicing dysregulation of specific mRNAs. Our study provides a knowledge base for properly tailoring future studies and identifies central excitatory synaptopathy as a key feature of motor circuit pathology in SMA. Graphical abstract Highlights • Comparison of detailed motor circuit pathology across three SMA mouse models • Motor circuit pathology correlates with dysregulation of specific mRNAs • Motor neuron death in severe and intermediate SMA models is p53-dependent • Central excitatory synaptopathy is the most conserved feature of SMA pathology Molecular biology; Neuroscience; Molecular neuroscience |
| Databáze: | OpenAIRE |
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