Central synaptopathy is the most conserved feature of motor circuit pathology across spinal muscular atrophy mouse models
Jannik M. Buettner,
Josiane K. Sime Longang,
Florian Gerstner,
Katharina S. Apel,
Beatriz Blanco-Redondo,
Leonie Sowoidnich,
Eva Janzen,
Tobias Langenhan,
Brunhilde Wirth,
Christian M. Simon
Affiliations
Jannik M. Buettner
Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig 04103, Germany
Josiane K. Sime Longang
Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig 04103, Germany
Florian Gerstner
Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig 04103, Germany
Katharina S. Apel
Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig 04103, Germany
Beatriz Blanco-Redondo
Rudolf Schönheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty, Leipzig University, Leipzig 04103, Germany
Leonie Sowoidnich
Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig 04103, Germany
Eva Janzen
Institute of Human Genetics, Center for Molecular Medicine Cologne, Institute for Genetics, University of Cologne, Cologne, Germany
Tobias Langenhan
Rudolf Schönheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty, Leipzig University, Leipzig 04103, Germany
Brunhilde Wirth
Institute of Human Genetics, Center for Molecular Medicine Cologne, Institute for Genetics, University of Cologne, Cologne, Germany; Center for Rare Diseases Cologne, University Hospital of Cologne, Cologne, Germany
Christian M. Simon
Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig 04103, Germany; Corresponding author
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.
