Proprioceptive synaptic dysfunction is a key feature in mice and humans with spinal muscular atrophy

Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by a varying degree of severity that is correlated with the reduction of SMN protein levels. Motor neuron degeneration and skeletal muscle atrophy are hallmarks of SMA, but it is unknown whether other mechanisms contribute to the spectrum of clinical phenotypes. Here, through a combination of physiological and morphological studies in mouse models and SMA patients, we identify dysfunction and loss of proprioceptive sensory synapses as key signatures of SMA pathology. We demonstrate that type 3 SMA patients exhibit impaired proprioception and that their proprioceptive synapses are dysfunctional as measured by the neurophysiological test of the Hoffmann reflex. We also show moderate loss of spinal motor neurons along with reduced excitatory afferent synapses and altered potassium channel expression in motor neurons from type 1 SMA patients. These are conserved pathogenic events found in both severely affected patients and mouse models. Lastly, we report that improved motor function and fatigability in ambulatory type 3 SMA patients and mouse models treated with SMN-inducing drugs are correlated with increased function of sensory-motor circuits that can be captured accurately by the Hoffmann reflex assay. Thus, sensory synaptic dysfunction is a clinically relevant event in SMA, and the Hoffmann reflex is a suitable assay to monitor disease progression and treatment efficacy of motor circuit pathology.

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Publication Details

Journal
Brain
Published
2025-02-19
DOI
https://doi.org/10.1093/brain/awaf074
Citations
9
Primary Topic
Neurogenetic and Muscular Disorders Research
Type
article
Field-Weighted Citation Impact
14.63

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article

Proprioceptive synaptic dysfunction is a key feature in mice and humans with spinal muscular atrophy

Christian M. Simon, Florian Gerstner, Scott Ensel, Livio Pellizzoni et al.
9 citations
Brain
Neurogenetic and Muscular Disorders Research
14.63
article

Proprioceptive synaptic dysfunction is a key feature in mice and humans with spinal muscular atrophy

Christian M. Simon, Florian Gerstner, Scott Ensel, Livio Pellizzoni, Panagiotis Kratimenos, Elvira Pirondini, Wendy K. Chung, Leonie Sowoidnich, Jose Luis García‐Giménez, George Z. Mentis, Darryl C. De Vivo, Serena Donadio, Nicolas Delestrée, Genís Prat-Ortega, Marco Capogrosso, María J. Carlini, Erick Carranza, Jannik M. Buettner, Louis H. Weimer, John G. Pagiazitis, Charlotte J. Sumner, Vanessa Dreilich
article en
9 citations

Abstract

Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by a varying degree of severity that is correlated with the reduction of SMN protein levels. Motor neuron degeneration and skeletal muscle atrophy are hallmarks of SMA, but it is unknown whether other mechanisms contribute to the spectrum of clinical phenotypes. Here, through a combination of physiological and morphological studies in mouse models and SMA patients, we identify dysfunction and loss of proprioceptive sensory synapses as key signatures of SMA pathology. We demonstrate that type 3 SMA patients exhibit impaired proprioception and that their proprioceptive synapses are dysfunctional as measured by the neurophysiological test of the Hoffmann reflex. We also show moderate loss of spinal motor neurons along with reduced excitatory afferent synapses and altered potassium channel expression in motor neurons from type 1 SMA patients. These are conserved pathogenic events found in both severely affected patients and mouse models. Lastly, we report that improved motor function and fatigability in ambulatory type 3 SMA patients and mouse models treated with SMN-inducing drugs are correlated with increased function of sensory-motor circuits that can be captured accurately by the Hoffmann reflex assay. Thus, sensory synaptic dysfunction is a clinically relevant event in SMA, and the Hoffmann reflex is a suitable assay to monitor disease progression and treatment efficacy of motor circuit pathology.

BrainVol. 148(8)
Boston Children's Hospital (US), Children's National (US), Harvard University (US), Johns Hopkins University (US), University of Pittsburgh (US), George Washington University (US), Johns Hopkins Medicine (US), Neurological Surgery (US), Columbia University (US), Leipzig University (DE)
Spinal Muscular Atrophy Foundation, Cure SMA, Roche España, Deutsche Forschungsgemeinschaft
Good health and well-being
Openalex Percentile: Top 1%
Neurogenetic and Muscular Disorders Research
14.63
DOIOpen Access PDFOpenAlex
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