TNF-α promotes alpha-synuclein propagation through stimulation of senescence-associated lysosomal exocytosis

Abstract

Cell-to-cell propagation of alpha-synuclein is thought to be the underlying mechanism of Parkinson's disease progression. Recent evidence suggests that inflammation plays an important role in the propagation of protein aggregates. However, the mechanism by which inflammation regulates the propagation of aggregates remains unknown. Here, using in vitro cultures, we found that soluble factors secreted from activated microglia promote cell-to-cell propagation of alpha-synuclein and further showed that among these soluble factors, TNF-alpha had the most robust stimulatory activity. Treatment of neurons with TNF-alpha triggered cellular senescence, as shown by transcriptomic analyses demonstrating induction of senescence-associated genes and immunoanalysis of senescence phenotype marker proteins. Interestingly, secretion of alpha-synuclein was increased in senescent neurons, reflecting acquisition of a senescence-associated secretory phenotype (SASP). Using vacuolin-1, an inhibitor of lysosomal exocytosis, and RNAi against rab27a, we demonstrated that the SASP was mediated by lysosomal exocytosis. Correlative light and electron microscopy and immunoelectron microscopy confirmed that propagating alpha-synuclein aggregates were present in electron-dense lysosome-like compartments. TNF-alpha promoted the SASP through stimulation of lysosomal exocytosis, thereby increasing the secretion of alpha-synuclein. Collectively, these results suggest that TNF-alpha is the major inflammatory factor that drives cell-to-cell propagation of alpha-synuclein by promoting the SASP and subsequent secretion of alpha-synuclein. Parkinson's disease: A vicious cycle of inflammation and protein aggregation A signaling protein known as a cytokine produced during inflammation promotes the spread of protein aggregates that cause Parkinson's disease. Several studies have suggested a role for inflammation in forming aggregates of the neuronal protein alpha-synuclein, the pathological hallmark of Parkinson's disease, but the exact mechanisms remain unclear. Now, Seung-Jae Lee at Seoul National University College of Medicine, South Korea, and co-workers have revealed a key role for an inflammatory cytokine called TNF-alpha. The team showed that TNF-alpha triggers cellular senescence, where cells undergo aging process, thereby stimulating the exocytosis mediated by lysosomes, or waste disposal system, in neurons. Over time, this results in an increased number of senescent cells, which secrete more alpha-synuclein than normal. The increased alpha-synuclein levels can in turn activate immune cells to sustain inflammation, setting up a feedback cycle to keep the disease progressing.