The accumulation of misfolded proteins is a common pathological feature of many neurodegenerative disorders, including synucleinopathies such as Parkinson's disease (PD), which is characterized by the presence of ␣-synuclein (␣-syn)-containing Lewy bodies. However, although recent studies have investigated ␣-syn accumulation and propagation in neurons, the molecular mechanisms underlying ␣-syn transmission have been largely unexplored. Here, we examined a monogenic form of synucleinopathy caused by loss-offunction mutations in lysosomal ATP13A2/PARK9. These studies revealed that lysosomal exocytosis regulates intracellular levels of ␣-syn in human neurons. Loss of PARK9 function in patient-derived dopaminergic neurons disrupted lysosomal Ca 2ϩ homeostasis, reduced lysosomal Ca 2ϩ storage, increased cytosolic Ca 2ϩ , and impaired lysosomal exocytosis. Importantly, this dysfunction in lysosomal exocytosis impaired ␣-syn secretion from both axons and soma, promoting ␣-syn accumulation. However, activation of the lysosomal Ca 2ϩ channel transient receptor potential mucolipin 1 (TRPML1) was sufficient to upregulate lysosomal exocytosis, rescue defective ␣-syn secretion, and prevent ␣-syn accumulation. Together, these results suggest that intracellular ␣-syn levels are regulated by lysosomal exocytosis in human dopaminergic neurons and may represent a potential therapeutic target for PD and other synucleinopathies.

The pathologic hallmark of Parkinson's disease is the accumulation of a-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 a-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 a-synuclein, and exhibited higher lysosomal degradation rates compared with neurons. Moreover, coculturing astrocytes and neurons led to decreased accumulation of a-synuclein in neurons and consequently diminished interneuronal transfer of a-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 a-synuclein pathology. Together, our results highlight the importance of lysosomal function in astrocytes in the pathogenesis of synucleinopathies.

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Parkinson’s disease (PD) is pathologically characterized by the deposition of a-synuclein (a-syn) containing Lewy bodies/neurites in both the central nervous system (CNS) and the peripheral nervous system (PNS). Recent evidence indicates the contribution of exosomes, nano-sized extracellular vesicles, to the dissemination of Lewy pathology in the PNS into the CNS and vice versa. We analyzed serum exosomes from patients with PD (n = 142), multiple system atrophy (MSA) (n = 18), progressive supranuclear palsy (PSP) (n = 28), rapid eye movement sleep behavior disorder (n = 31), and controls (n = 105). Although the number of exosomes significantly decreased in PD compared to controls (p = 0.002), the filamentous α-syn in exosomes quantified by our ELISA system significantly increased in PD compared to controls (p < 0.0001) and compared to MSA (p = 0.03) or PSP (p = 0.04). Further analysis revealed that exosomes facilitate the propagation of filamentous α-syn between neurons and from the PNS to the CNS. These results highlight that the serum exosomal a-syn filaments may reflect peripheral Lewy pathology and that exosomes can enhance the propagation into the CNS.