image: Pcyt2 is specifically expressed in subsets of neuroglia. Replacing the Pcyt2 minor intron with a major intron in the Drosophila SMA model substantially reverses multiple SMA‑associated pathological phenotypes.
Credit: ©Science Bulletin
Spinal muscular atrophy (SMA) is a severe hereditary neuromuscular disease primarily caused by insufficient expression of the survival motor neuron (SMN) protein. While SMN deficiency is recognized as the primary cause of SMA, the downstream key molecular and cellular mechanisms mediating disease initiation and progression still remain poorly understood. Conventional views have regarded motor neurons as the principal cell type damaged in SMA, yet accumulating evidence indicates that neuroglia also participate in disease pathogenesis.
Recently, the research team led by Yong-Zhen Xu and Yu-Jie Fan from Wuhan University published a research article entitled Impaired splicing of a conserved Pcyt2 minor intron in specific neuroglia contributes to spinal muscular atrophy in Science Bulletin. Focusing on Pcyt2, a lipid‑metabolism gene identified in their prior screen, the team carried out in‑depth mechanistic investigations using Drosophila and mouse SMA models. They revealed that aberrant splicing of the conserved Pcyt2 minor intron within specific neuroglia acts as a critical driver of SMA pathogenesis, offering new insights for glia‑targeted diagnosis and treatment of SMA and related neurodegenerative disorders.
The SMN protein participates in the biogenesis and assembly of spliceosomes. In higher organisms, there are two classes of spliceosomes—the major and the minor—which are responsible for catalyzing the splicing of the vast majority and a very small minority of introns, respectively. Loss of SMN markedly diminishes minor spliceosome activity and consequently compromises splicing of the Pcyt2 minor intron. Using gene‑editing technology, the researchers precisely replaced the endogenous Pcyt2 minor intron with a length‑matched major intron in SMA Drosophila models. This manipulation restored splicing of Pcyt2 minor intron and concurrent recovery of PCYT2 protein abundance. Notably, hallmark SMA pathological phenotypes including impaired locomotor capacity, muscle atrophy, and reduced neuromuscular junction density were significantly ameliorated, demonstrating that defective splicing of the Pcyt2 minor intron represents a key pathogenic trigger for SMA.
By combining immunostaining with glia-specific reporter tools, they further localized the pathogenic effects to perineurial and ensheathing glia within the Drosophila central nervous system. Specifically induced Pcyt2 expression in these two glial populations significantly rescued locomotor deficits in SMA flies. Further electrophysiological assays validated that restoring glial Pcyt2 expression rescued synaptic transmission at neuromuscular junctions. To test for evolutionary conservation of this axis, we established an oligodendrocyte-specific Smn-deficient mouse line, and found that Pcyt2 minor intron retention occurred similarly in this context. Supplementation of Pcyt2 specifically in oligodendrocytes via AAV significantly ameliorated diverse SMA-related pathologies, ranging from weight loss and motor dysfunction to muscle atrophy and neuromuscular junction endplate defects, confirming that the Smn-Pcyt2 regulatory pathway is conserved in mammals.
Furthermore, Pcyt2 mutations, splicing defects, and expression dysregulation are observed across various other neuromuscular and neurodegenerative disorders, often accompanied by disrupted glial lipid metabolism, implying that the Pcyt2-glial lipid metabolism axis may represent a shared therapeutic target with promising implications.
About the Authors
The Yong-Zhen Xu and Yu-Jie Fan laboratory at Wuhan University focuses on RNA splicing regulation in development and disease, with recent efforts centering on the regulatory functions of highly conserved introns and intronic elements under physiological and pathological contexts. Ni Long and Hui-Yi Zhao are co‑first authors of this work.
This research was supported by the National Natural Science Foundation of China and the Natural Science Foundation of Hubei Province.
Journal
Science Bulletin