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Neuron, Published:March 01, 2023 | https://doi.org/10.1016/j.neuron.2023.02.004 A spinal muscular atrophy modifier implicates the SMN protein in SNARE complex assembly at neuromuscular synapses

Jeong-Ki Kim,^1,4,11 Narendra N. Jha,^1,4,11 Tomoyuki Awano,^1,4 Charlotte Caine,^1,4 Kishore Gollapalli,^1,4 Emily Welby,⁶ Seung-Soo Kim,³ Andrea Fuentes-Moliz,⁷ Xueyong Wang,⁸ Zhihua Feng,⁹ Fusako Sera,¹⁰ Taishi Takeda,^1,4 Shunichi Homma,¹⁰ Chien-Ping Ko,⁹ Lucia Tabares,⁷ Allison D. Ebert,⁶ Mark M. Rich,⁸ and Umrao R. Monani^1,2,4,5,12,*

¹Department of Neurology, New York, NY, USA
²Department of Pathology & Cell Biology, New York, NY, USA
³Department of Obstetrics and Gynecology, New York, NY, USA
⁴Center for Motor Neuron Biology & Disease, New York, NY, USA
⁵Colleen Giblin Research Laboratory, Columbia University Irving Medical Center, New York, NY 10032, USA
⁶Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA
⁷Department of Medical Physiology and Biophysics, University of Seville School of Medicine, 41009, Seville, Spain
⁸Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, OH 45435, USA
⁹Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
¹⁰Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
¹¹These authors contributed equally
¹²Lead contact

*Correspondence: Umrao R. Monani

Abstract

Reduced survival motor neuron (SMN) protein triggers the motor neuron disease, spinal muscular atrophy (SMA). Restoring SMN prevents disease, but it is not known how neuromuscular function is preserved. We used model mice to map and identify an Hspa8^G470R synaptic chaperone variant, which suppressed SMA. Expression of the variant in the severely affected mutant mice increased lifespan >10-fold, improved motor performance, and mitigated neuromuscular pathology. Mechanistically, Hspa8^G470R altered SMN2 splicing and simultaneously stimulated formation of a tripartite chaperone complex, critical for synaptic homeostasis, by augmenting its interaction with other complex members. Concomitantly, synaptic vesicular SNARE complex formation, which relies on chaperone activity for sustained neuromuscular synaptic transmission, was found perturbed in SMA mice and patient-derived motor neurons and was restored in modified mutants. Identification of the Hspa8^G470R SMA modifier implicates SMN in SNARE complex assembly and casts new light on how deficiency of the ubiquitous protein causes motor neuron disease.

논문정보

형식Research article
게재일2023년 03월 (BRIC 등록일 2023-04-07)
연구진국외 연구진
분야 생명과학 > 신경생물학

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