A spinal muscular atrophy modifier implicates the SMN protein in SNARE complex assembly at neuromuscular synapses. Neuron 2023 May 03;111(9):1423-1439.e4
Date
03/03/2023Pubmed ID
36863345Pubmed Central ID
PMC10164130DOI
10.1016/j.neuron.2023.02.004Scopus ID
2-s2.0-85150290633 (requires institutional sign-in at Scopus site) 9 CitationsAbstract
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 Hspa8G470R 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, Hspa8G470R 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 Hspa8G470R SMA modifier implicates SMN in SNARE complex assembly and casts new light on how deficiency of the ubiquitous protein causes motor neuron disease.
Author List
Kim JK, Jha NN, Awano T, Caine C, Gollapalli K, Welby E, Kim SS, Fuentes-Moliz A, Wang X, Feng Z, Sera F, Takeda T, Homma S, Ko CP, Tabares L, Ebert AD, Rich MM, Monani URAuthor
Allison D. Ebert PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsDisease Models, Animal
Mice
Motor Neurons
Muscular Atrophy, Spinal
SNARE Proteins
Survival of Motor Neuron 1 Protein
Synapses
Synaptic Transmission
Transcription Factors
