Seattle Children's Hospital Research Institute, Integrative Center for Brain Research, Seattle, Washington, USA.
King's College London, Regeneration Group, The Wolfson Centre for Age-Related Diseases, Guy's Campus, London Bridge, London, UK.
Exp Neurol. 2020 Jun;328:113276. doi: 10.1016/j.expneurol.2020.113276. Epub 2020 Mar 4.
Chondroitin sulfate proteoglycans (CSPGs), extracellular matrix molecules that increase dramatically following a variety of CNS injuries or diseases, have long been known for their potent capacity to curtail cell migrations as well as axon regeneration and sprouting. The inhibition can be conferred through binding to their major cognate receptor, Protein Tyrosine Phosphatase Sigma (PTPσ). However, the precise mechanisms downstream of receptor binding that mediate growth inhibition have remained elusive. Recently, CSPGs/PTPσ interactions were found to regulate autophagic flux at the axon growth cone by dampening the autophagosome-lysosomal fusion step. Because of the intense interest in autophagic phenomena in the regulation of a wide variety of critical cellular functions, we summarize here what is currently known about dysregulation of autophagy following spinal cord injury, and highlight this critical new mechanism underlying axon regeneration failure. Furthermore, we review how CSPGs/PTPσ interactions influence plasticity through autophagic regulation and how PTPσ serves as a switch to execute either axon outgrowth or synaptogenesis. This has exciting implications for the role CSPGs play not only in axon regeneration failure after spinal cord injury, but also in neurodegenerative diseases where, again, inhibitory CSPGs are upregulated.
软骨素硫酸盐蛋白聚糖（CSPGs）是细胞外基质分子，在多种中枢神经系统损伤或疾病后会大量增加，长期以来，它们具有抑制细胞迁移以及轴突再生和发芽的强大能力而为人所知。这种抑制作用可以通过与主要同源受体蛋白酪氨酸磷酸酶 Sigma（PTPσ）结合来实现。然而，介导生长抑制的受体结合下游的确切机制仍然难以捉摸。最近，发现 CSPGs/PTPσ 相互作用通过抑制自噬体 - 溶酶体融合步骤来调节轴突生长锥中的自噬通量。由于人们对自噬现象在调节广泛的各种关键细胞功能中的作用非常感兴趣，我们在这里总结了目前已知的脊髓损伤后自噬失调的情况，并强调了这一关键的新机制是轴突再生失败的基础。此外，我们回顾了 CSPGs/PTPσ 相互作用如何通过自噬调节来影响可塑性，以及 PTPσ 如何作为执行轴突生长或突触发生的开关。这对于 CSPGs 不仅在脊髓损伤后轴突再生失败中，而且在神经退行性疾病中发挥的作用具有令人兴奋的意义，在这些疾病中，抑制性 CSPGs 也被上调。
