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

Authors

Christian M. Simon, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA.
Nicolas Delestrée, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA.
Jacqueline Montes, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA.
Leonie Sowoidnich, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA.
Florian Gerstner, Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig, Saxony 04103, Germany.
Erick Carranza, Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Jannik M. Buettner, Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig, Saxony 04103, Germany.
John G. Pagiazitis, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA.
Genis Prat-Ortega, Rehab Neural Engineering Labs, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Scott Ensel, Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Serena Donadio, Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Vanessa Dreilich, Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig, Saxony 04103, Germany.
Maria J. Carlini, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA.
Jose L. Garcia, Department of Neurology, Columbia University, New York, NY 10032, USA.
Panagiotis Kratimenos, Center for Neuroscience Research, Children's National Research Institute, Washington, DC 20012, USA.
Wendy K. Chung, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Charlotte J. Sumner, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Louis H. Weimer, Department of Neurology, Columbia University, New York, NY 10032, USA.
Elvira Pirondini, Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Marco Capogrosso, Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Livio Pellizzoni, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA.
Darryl C. De Vivo, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA.
George Z. Mentis, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA.

Document Type

Journal Article

Publication Date

8-1-2025

Journal

Brain : a journal of neurology

Volume

148

Issue

8

DOI

10.1093/brain/awaf074

Keywords

motor neuron; neurodegenerative disease; proprioception; sensory synapses; sensory–motor circuit; spinal muscular atrophy

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.

APA Citation

Simon, Christian M.; Delestrée, Nicolas; Montes, Jacqueline; Sowoidnich, Leonie; Gerstner, Florian; Carranza, Erick; Buettner, Jannik M.; Pagiazitis, John G.; Prat-Ortega, Genis; Ensel, Scott; Donadio, Serena; Dreilich, Vanessa; Carlini, Maria J.; Garcia, Jose L.; Kratimenos, Panagiotis; Chung, Wendy K.; Sumner, Charlotte J.; Weimer, Louis H.; Pirondini, Elvira; Capogrosso, Marco; Pellizzoni, Livio; De Vivo, Darryl C.; and Mentis, George Z., "Proprioceptive synaptic dysfunction is a key feature in mice and humans with spinal muscular atrophy" (2025). GW Authored Works. Paper 7864.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/7864

Department

Pediatrics