Increased lysosomal exocytosis induced by lysosomal Ca²+ channel agonists protects human dopaminergic neurons from α-synuclein toxicity

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 α-synuclein (α-syn)-containing Lewy bodies. However,althoughrecentstudieshaveinvestigatedα-synaccumulationandpropagationinneurons,themolecularmechanismsunderlying α-syn transmission have been largely unexplored. Here, we examined a monogenic form of synucleinopathy caused by loss-of-function mutations in lysosomal ATP13A2/PARK9. These studies revealed that lysosomal exocytosis regulates intracellular levels of α-syn in human neurons. Loss of PARK9 function in patient-derived dopaminergic neurons disrupted lysosomal Ca²⁺ homeostasis, reduced lysosomal Ca²⁺ storage, increased cytosolic Ca²⁺, and impaired lysosomal exocytosis. Importantly, this dysfunction in lysosomal exocytosis impaired α-syn secretion from both axons and soma, promoting α-syn accumulation. However, activation of the lysosomal Ca²⁺ channel transient receptor potential mucolipin 1 (TRPML1) was sufficient to upregulate lysosomal exocytosis, rescue defective α-syn secretion, and prevent α-syn accumulation. Together, these results suggest that intracellular α-syn levels are regulated by lysosomalexocytosisinhumandopaminergicneuronsandmayrepresentapotentialtherapeutictargetforPDandothersynucleinopathies.