IRCCS San Camillo Hospital, Venice, Italy.
Department of Biology, University of Padova, Padua, Italy.
Mol Neurodegener. 2024 Jan 16;19(1):5. doi: 10.1186/s13024-024-00703-1.
Protein misfolding and accumulation defines a prevailing feature of many neurodegenerative disorders, finally resulting in the formation of toxic intra- and extracellular aggregates. Intracellular aggregates can enter the extracellular space and be subsequently transferred among different cell types, thus spreading between connected brain districts.Although microglia perform a predominant role in the removal of extracellular aggregated proteins, mounting evidence suggests that astrocytes actively contribute to the clearing process. However, the molecular mechanisms used by astrocytes to remove misfolded proteins are still largely unknown.Here we first provide a brief overview of the progressive transition from soluble monomers to insoluble fibrils that characterizes amyloid proteins, referring to α-Synuclein and Tau as archetypical examples. We then highlight the mechanisms at the basis of astrocyte-mediated clearance with a focus on their potential ability to recognize, collect, internalize and digest extracellular protein aggregates. Finally, we explore the potential of targeting astrocyte-mediated clearance as a future therapeutic approach for the treatment of neurodegenerative disorders characterized by protein misfolding and accumulation.
蛋白质错误折叠和积累定义了许多神经退行性疾病的主要特征，最终导致有毒的细胞内和细胞外聚集体的形成。细胞内聚集体可以进入细胞外空间，并在不同的细胞类型之间进行后续转移，从而在连接的脑区之间传播。虽然小胶质细胞在清除细胞外聚集的蛋白质方面发挥着主要作用，但越来越多的证据表明星形胶质细胞积极参与清除过程。然而，星形胶质细胞用于清除错误折叠蛋白质的分子机制在很大程度上仍然未知。在这里，我们首先简要概述了特征性淀粉样蛋白从可溶性单体到不溶性纤维的渐进转变，以α-突触核蛋白和 Tau 为例。然后，我们强调了星形胶质细胞介导的清除的基础机制，重点是它们识别、收集、内化和消化细胞外蛋白质聚集体的潜在能力。最后，我们探讨了靶向星形胶质细胞介导的清除作为治疗以蛋白质错误折叠和积累为特征的神经退行性疾病的未来治疗方法的潜力。
