RT Journal Article SR Electronic T1 Astrocytes Protect Human Dopaminergic Neurons from α-Synuclein Accumulation and Propagation JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 8618 OP 8628 DO 10.1523/JNEUROSCI.0954-20.2020 VO 40 IS 45 A1 Tsunemi, Taiji A1 Ishiguro, Yuta A1 Yoroisaka, Asako A1 Valdez, Clarissa A1 Miyamoto, Kengo A1 Ishikawa, Keiichi A1 Saiki, Shinji A1 Akamatsu, Wado A1 Hattori, Nobutaka A1 Krainc, Dimitri YR 2020 UL http://www.jneurosci.org/content/40/45/8618.abstract AB The pathologic hallmark of Parkinson's disease is the accumulation of α-synuclein-containing Lewy bodies/neurites almost exclusively in neurons, and rarely in glial cells. However, emerging evidence suggests that glia such as astrocytes play an important role in the development of α-synuclein pathology. Using induced pluripotent stem-derived dopaminergic neurons and astrocytes from healthy subjects and patients carrying mutations in lysosomal ATP13A2, a monogenic form of synucleinopathy, we found that astrocytes rapidly internalized α-synuclein, and exhibited higher lysosomal degradation rates compared with neurons. Moreover, coculturing astrocytes and neurons led to decreased accumulation of α-synuclein in neurons and consequently diminished interneuronal transfer of α-synuclein. These protective functions of astrocytes were attenuated by ATP13A2 deficiency, suggesting that the loss of ATP13A2 function in astrocytes at least partially contributes to neuronal α-synuclein pathology. Together, our results highlight the importance of lysosomal function in astrocytes in the pathogenesis of synucleinopathies.SIGNIFICANCE STATEMENT While most neurodegenerative disorders are characterized by the accumulation of aggregated mutant proteins exclusively in neurons, the contribution of glial cells in this process remains poorly explored. Here, we demonstrate that astrocytes contribute to the removal of extracellular α-synuclein and that disruption of this pathway caused by mutations in the Parkinson's disease-linked gene ATP13A2 result in α-synuclein accumulation in human dopaminergic neurons. We found that astrocytes also protect neurons from α-synuclein propagation, whereas ATP13A2 deficiency in astrocytes compromises this protective function. These results highlight astrocyte-mediated α-synuclein clearance as a potential therapeutic target in disorders characterized by the accumulation of α-synuclein, including Parkinson's disease.