Journal
JOURNAL OF NEUROSCIENCE
Volume 39, Issue 29, Pages 5760-5772Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3085-18.2019
Keywords
alpha synuclein; dopaminergic neuron; Kufor-Rakeb syndrome; lysosomal exocytosis; Parkinson's disease; TRPML1
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Funding
- National Institutes of Health [R37 NS096241]
- Japan Society for the Promotion of Science KAKENHI [16H07185, 18K07510]
- Brain Research Foundation
- Juntendo University Research Institute for Diseases of Old Age and Environmental & Gender-Specific Medicine
- Practical Research Project for Rare/Intractable Diseases from AMED [JP17ek0109244]
- Strategic Research Foundation
- Grants-in-Aid for Scientific Research [18K07510, 16H07185] Funding Source: KAKEN
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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 alpha-synuclein (alpha-syn)-containing Lewy bodies. However, although recent studies have investigated alpha-syn accumulation and propagation in neurons, the molecular mechanisms underlying alpha-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 alpha-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 alpha-syn secretion from both axons and soma, promoting alpha-syn accumulation. However, activation of the lysosomal Ca2+ channel transient receptor potential mucolipin 1 (TRPML1) was sufficient to upregulate lysosomal exocytosis, rescue defective alpha-syn secretion, and prevent alpha-syn accumulation. Together, these results suggest that intracellular alpha-syn levels are regulated by lysosomal exocytosis in human dopaminergic neurons and may represent a potential therapeutic target for PD and other synucleinopathies.
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