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

Taiji Tsunemi, Tamara Perez-Rosello, Yuta Ishiguro, Asako Yoroisaka, Sohee Jeon, Kana Hamada, Malini Rammonhan, Yvette C. Wong, Zhong Xie, Wado Akamatsu, Joe Mazzulli, Dalton James Surmeier Jr, Nobutaka Hattori, Dimitri Krainc

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)5760-5772
Number of pages13
JournalJournal of Neuroscience
Volume39
Issue number29
DOIs
StatePublished - Jul 17 2019

Keywords

  • Alpha synuclein
  • Dopaminergic neuron
  • Kufor–Rakeb syndrome
  • Lysosomal exocytosis
  • Parkinson’s disease
  • TRPML1

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint

Dive into the research topics of 'Increased lysosomal exocytosis induced by lysosomal Ca2+ channel agonists protects human dopaminergic neurons from α-synuclein toxicity'. Together they form a unique fingerprint.

Cite this