Direct Transfer of α-Synuclein from Neuron to Astroglia Causes Inflammatory Responses in Synucleinopathies

Abstract

Abnormal neuronal aggregation of ␣-synuclein is implicated in the development of many neurological disorders, including Parkinson disease and dementia with Lewy bodies. Glial cells also show extensive ␣-synuclein pathology and may contribute to disease progression. However, the mechanism that produces the glial ␣-synuclein pathology and the interaction between neurons and glia in the disease-inflicted microenvironment remain unknown. Here, we show that ␣-synuclein proteins released from neuronal cells are taken up by astrocytes through endocytosis and form inclusion bodies. The glial accumulation of ␣-synuclein through the transmission of the neuronal protein was also demonstrated in a transgenic mouse model expressing human ␣-synuclein. Furthermore, astrocytes that were exposed to neuronal ␣-synuclein underwent changes in the gene expression profile reflecting an inflammatory response. Induction of pro-inflammatory cytokines and chemokines correlated with the extent of glial accumulation of ␣-synuclein. Together, these results suggest that astroglial ␣-synuclein pathology is produced by direct transmission of neuronal ␣-synuclein aggregates, causing inflammatory responses. This transmission step is thus an important mediator of pathogenic glial responses and could qualify as a new therapeutic target.

Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

“…Interestingly, along with the neuronal damage observed, we also detected reactive astrocytes in our cultures. Our findings are consistent with studies demonstrating that incubation of astrocytic cultures with neuronal-derived aSyn triggered aSyn aggregation in these cells, along with changes in the levels of cytokines and chemokines, a sign of an inflammatory response (55). In our study, the inflammatory response we observe is intimately linked to neuronal damage but independent of inclusion formation.…”

ADP-ribosylation Factor 6 (ARF6) Bidirectionally Regulates Dendritic Spine Formation Depending on Neuronal Maturation and Activity

“…1 A). We defined the developing stage of a neuron as when spine development shows exponential growth (DIV 11-15), whereas the mature stage was when it reaches a plateau (DIV [17][18][19][20]. The ratio of spines versus filopodia also increased as neurons matured (Fig.…”

“…Statistical Analysis of Gene Expression Data-Using the normalized log 2 intensities, the differentially expressed genes (DEGs) between two conditions were identified as described previously (19). Briefly, 1) Student's t test and log 2 median ratio test were performed to compute T values and log 2 median ratios for all the genes.…”

Characterization of gene expression and activated signaling pathways in solid-pseudopapillary neoplasm of pancreas

“…15 Using the normalized intensities, differentially expressed genes between non-neoplastic pancreatic tissue and pancreatic tumors (solid-pseudopapillary neoplasm, neuroendocrine tumor, or pancreatic adenocarcinoma) were determined using the integrated statistical method previously reported. 16 Briefly, (1) two independent tests were performed: Student's t-test and log 2 -median-ratio test; (2) adjusted P-values from each test were computed using an empirical distribution of the null hypothesis that the means of the genes were not different, which was obtained from random permutations of the samples; (3) the P values from the two tests were combined to compute the overall P-values using Stouffer's method 17 and (4) differentially expressed genes were selected as those with Po0.01 and a fold change 41.5. Finally, functional enrichment analysis of the differentially expressed genes was performed using DAVID software 18 to identify GO biological processes and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways represented by the genes in individual clusters with statistical significance (Supplementary Figure 2A and B).…”