Increased Lysosomal Exocytosis Induced by Lysosomal Ca²⁺ Channel Agonists Protects Human Dopaminergic Neurons from α-Synuclein Toxicity

Abstract

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.

Lysosomal Exocytosis, Exosome Release and Secretory Autophagy: The Autophagic- and Endo-Lysosomal Systems Go Extracellular

“…Based on these findings, induction of lysosomal exocytosis to promote cellular clearance has been proposed as an alternative therapeutic strategy to treat not only LSDs, but also other pathological conditions characterized by undigested substrates accumulation and overloaded dysfunctional lysosomes, such as several common neurodegenerative disorders [2,32]. For instance, promising results have been recently obtained by increasing lysosomal exocytosis with lysosomal Ca 2+ channel TRPML1 agonists in iPSC-derived dopaminergic neurons from PARK9 mutated Parkinson's disease patients [33]. Authors showed that lysosomal exocytosis is involved in clearing intracellular α-synuclein in human dopaminergic neurons and that mutations in PARK9 contribute to the α-synuclein storage.…”

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA)

“…Loss of ATP13A2 function is also associated with α-syn accumulation [ 166 , 167 ]. IPSC-derived dopaminergic neurons from KRD exhibit decreased secretion of α-syn from the axon and the cell body, as well as a disruption of the lysosomal Ca 2+ homeostasis.…”

“…IPSC-derived dopaminergic neurons from KRD exhibit decreased secretion of α-syn from the axon and the cell body, as well as a disruption of the lysosomal Ca 2+ homeostasis. Enhancing lysosomal exocytosis by overexpression of ATP13A2 helps to control the α-syn levels [ 166 , 167 ].…”

Pathophysiological Role of Transient Receptor Potential Mucolipin Channel 1 in Calcium-Mediated Stress-Induced Neurodegenerative Diseases

“…Indeed, PARK9 regulates lysosomal exocytosis, a pathway that could be potentiated to reduce α-synuclein accumulation. Tsunemi demonstrated that TRPML1 agonists are able to increase lysosomal exocytosis, thus impairing α-synuclein intracellular levels (Tsunemi et al, 2019).…”