Non-cell-autonomous actions of α-synuclein: Implications in glial synucleinopathies

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HighlightsSynucleinopathy lesions are pathological characteristics of many neurological disorders.In synucleinopathy diseases, abnormal deposition of α-synuclein aggregates occurs not only in neurons but also in glial cells.α-synuclein can be secreted from neurons and the extracellular α-synuclein can elicitpathological changes in glial cells.Glial cells do express α-synuclein in low levels.Debate exists as to the source of α-synuclein that triggers glial responses and pathologies.Many neurodegenerative diseases are derived from the combined consequences of genetic and environmental factors. One of the common features implicated in the neurodegenerative processes is aggregation of disease-specific neuronal proteins. These proteins are accumulated not only directly in neurons, but also indirectly involve glial cells. Whereas the focus of research has been directed towards the impacts of protein aggregation upon neurons, the influence that it exerts on glial cells has been relatively overlooked. Recent studies, however, provide strong evidence on pathogenic responses of glial cells originated from the neuron-derived protein aggregates. Here, we critically examine the latest advancement in investigating how glial cells are activated in neurodegenerative disorders that are associated with α-synuclein aggregates. Often referred to as synucleinopathies, these include Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. To further illustrate, we would discuss paracrine actions of α-synuclein aggregates secreted from neuronal cells in promoting pathogenic reactions from various types of glia and evaluate the non-cell-autonomous mechanism compared to a cell-autonomous one. Such analyses of the impacts of glial responses in neurodegenerative diseases, in the long term, could be further utilized in developing different treatments of the diseases and potentially discovering new drugs.

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