Fig. 1

Astrocyte dysfunction induced by transmitted α-synuclein and PD-associated gene modulation. Astrocytes receive large amounts of α-synuclein released from dopaminergic neurons in the forms of monomeric and aggregated species. Both the proinflammatory phenotype and the reactive antigen (cross)-presenting phenotype of astrocytes are induced by transmitted α-synuclein. Astrocytes with PARK7 mutations display a loss of anti-inflammatory function and enhanced proinflammatory responses. Transmitted α-synuclein impairs the astrocytic degradation capability and facilitates α-synuclein accumulation, and this can be aggravated by LRRK2, GBA1 or ATP13A2 mutations. Alpha-synuclein accumulation in astrocytes also induces mitochondrial dysfunction and endoplasmic reticulum stress. PINK1 and PRKN mutations are involved in mitophagy deficiency and lead to dysfunctional mitochondria. Astrocytic ER stress might be a coordinator of the effects of PRKN, LRRK2 and PLA2G6 mutations. Iron transport in astrocytes, especially that via the iron exporter ferroportin and its ligand hepcidin, is pivotal for iron homeostasis in the surroundings. The pathological processes that occur in dysfunctional astrocytes, including protein degradation dysfunction, inflammatory response, ER stress, mitochondrial dysfunction, and iron metabolism disturbance, could be triggered by transmitted α-synuclein; moreover, the aggregated α-synuclein in astrocytes could be transferred to adjacent astrocytes, microglia and even neurons, thereby spreading the overall synucleinopathy and neurodegeneration