Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), D-81377, Munich, Germany.
Department of Neurology, Technical University of Munich, D-81675, Munich, Germany.
Cell Death Dis. 2018 Jul 9;9(7):757. doi: 10.1038/s41419-018-0816-2.
Accumulation of pathological α-synuclein aggregates plays a major role in Parkinson's disease. Macroautophagy is a mechanism to degrade intracellular protein aggregates by wrapping them into autophagosomes, followed by fusion with lysosomes. We had previously shown that pharmacological activation of macroautophagy protects against α-synuclein-induced toxicity in human neurons. Here, we hypothesized that inhibition of macroautophagy would aggravate α-synuclein-induced cell death.Unexpectedly, inhibition of autophagosome formation by silencing of ATG5 protected from α-synuclein-induced toxicity. Therefore, we studied alternative cellular mechanisms to compensate for the loss of macroautophagy. ATG5 silencing did not affect the ubiquitin-proteasome system, chaperone systems, chaperone-mediated autophagy, or the unfolded protein response. However, ATG5 silencing increased the secretion of α-synuclein via exosomes. Blocking exosomal secretion exacerbated α-synuclein-induced cell death.We conclude that exosomal secretion of α-synuclein is increased after impaired formation of autophagosomes to reduce the intracellular α-synuclein burden. This compensatory mechanism prevents α-synuclein-induced neuronal cell death.
病理性 α-突触核蛋白聚集体的积累在帕金森病中起着主要作用。巨自噬是一种通过将细胞内蛋白质聚集体包裹到自噬体中，然后与溶酶体融合来降解它们的机制。我们之前曾表明，巨自噬的药理学激活可防止人神经元中 α-突触核蛋白诱导的毒性。在这里，我们假设巨自噬的抑制会加重 α-突触核蛋白诱导的细胞死亡。出乎意料的是，通过沉默 ATG5 抑制自噬体形成可保护免受 α-突触核蛋白诱导的毒性。因此，我们研究了替代细胞机制来补偿巨自噬的丧失。ATG5 沉默不影响泛素-蛋白酶体系统、伴侣系统、伴侣介导的自噬或未折叠蛋白反应。然而，ATG5 沉默通过外泌体增加了 α-突触核蛋白的分泌。阻断外泌体分泌加剧了 α-突触核蛋白诱导的细胞死亡。我们得出结论，自噬体形成受损后，α-突触核蛋白通过外泌体的分泌增加，以减少细胞内 α-突触核蛋白负担。这种补偿机制可防止 α-突触核蛋白诱导的神经元细胞死亡。
