Boosting neuregulin 1 type-III expression hastens SMA motor axon maturation.
Boosting neuregulin 1 type-III expression hastens SMA motor axon maturation.
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DOI：
10.1186/s40478-023-01551-8
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发表时间：
2023-03-30
影响因子：
7.1
通讯作者：
Sumner, Charlotte J.
中科院分区：
文献类型：
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作者：
Kong, Lingling;Hassinan, Cera W.;Gerstner, Florian;Buettner, Jannik M.;Petigrow, Jeffrey B.;Valdivia, David O.;Chan-Cortes, Michelle H.;Mistri, Amy;Cao, Annie;McGaugh, Scott Alan;Denton, Madeline;Brown, Stephen;Ross, Joshua;Schwab, Markus H.;Simon, Christian M.;Sumner, Charlotte J.
关键词：
轴突和雪旺细胞之间的细胞间通讯对于获得轴突成熟所需的复杂形态步骤至关重要。在早期起病的运动神经元病-脊髓性肌萎缩症(SMA)中，许多运动神经轴突没有被雪旺细胞包裹，也没有足够的径向生长成为有髓鞘。这些发育受阻的运动轴突功能失调，容易迅速退化，限制了目前SMA疗法的疗效。我们推测，加速SMA运动神经轴突成熟将改善其功能，减少疾病特征。外周轴突发育的主要调节因子是NRG1-III(NRG1-III)。它表达在轴突表面，与雪旺细胞受体相互作用，介导轴突包膜和髓鞘形成。我们检测了人和小鼠SMA组织中NRG1mRNA和蛋白的表达水平，并观察到SMA脊髓和腹侧的NRG1mRNA和蛋白表达减少，但背根轴突没有表达。为了确定神经元NRG1III过表达对SMA运动神经元轴突发育的影响，我们将NRG1III过表达的小鼠培育成SMA∆7小鼠。在新生儿，NRG1-III的高表达增加了SMA腹根的大小以及轴突的分离、直径和髓鞘形成，从而改善了运动轴传导速度。NRG1-III不能防止远端轴突变性，也不能改善轴突电生理、运动行为或老年小鼠的存活率。总之，这些发现表明，早期SMA运动轴突发育障碍可以通过独立于SMN替代的分子策略得到改善，为未来的SMA联合治疗方法提供了希望。网上版载有补充材料，可在10.1186/s40478-023-023-8查阅。
Intercellular communication between axons and Schwann cells is critical for attaining the complex morphological steps necessary for axon maturation. In the early onset motor neuron disease spinal muscular atrophy (SMA), many motor axons are not ensheathed by Schwann cells nor grow sufficiently in radial diameter to become myelinated. These developmentally arrested motor axons are dysfunctional and vulnerable to rapid degeneration, limiting efficacy of current SMA therapeutics. We hypothesized that accelerating SMA motor axon maturation would improve their function and reduce disease features. A principle regulator of peripheral axon development is neuregulin 1 type III (NRG1-III). Expressed on axon surfaces, it interacts with Schwann cell receptors to mediate axon ensheathment and myelination. We examined NRG1 mRNA and protein expression levels in human and mouse SMA tissues and observed reduced expression in SMA spinal cord and in ventral, but not dorsal root axons. To determine the impact of neuronal NRG1-III overexpression on SMA motor axon development, we bred NRG1-III overexpressing mice to SMA∆7 mice. Neonatally, elevated NRG1-III expression increased SMA ventral root size as well as axon segregation, diameter, and myelination resulting in improved motor axon conduction velocities. NRG1-III was not able to prevent distal axonal degeneration nor improve axon electrophysiology, motor behavior, or survival of older mice. Together these findings demonstrate that early SMA motor axon developmental impairments can be ameliorated by a molecular strategy independent of SMN replacement providing hope for future SMA combinatorial therapeutic approaches. The online version contains supplementary material available at 10.1186/s40478-023-01551-8.
影响因子：
--
作者：
Buettner JM;Kirmann T;Mentis GZ;Hallermann S;Simon CM
通讯作者：
Simon CM