http://www.jneurosci.org/content/early/2019/05/16/JNEUROSCI.3085-18.2019
https://www.ncbi.nlm.nih.gov/pubmed/31097622?dopt=Abstract
TITLE:
Increased lysosomal exocytosis induced by lysosomal Ca2+ channel agonists protects human dopaminergic neurons from α-synuclein toxicity.
DESCRIPTION:
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Increased lysosomal exocytosis induced by lysosomal Ca2+ channel agonists protects human dopaminergic neurons from α-synuclein toxicity.
J Neurosci. 2019 May 16;:
Authors: Tsunemi T, Perez-Rosello T, Ishiguro Y, Yoroisaka A, Jeon S, Hamada K, Krishna Vangipuram Suresh M, Wong YC, Xie Z, Akamatsu W, Mazzulli JR, Surmeier DJ, Hattori N, Krainc D
Abstract
The accumulation of misfolded proteins is a common pathological feature of many neurodegenerative disorders, including synucleinopathies such as Parkinson’s disease which is characterized by the presence of α-synuclein (α-syn) containing Lewy bodies. However, while recent studies have investigated α-syn accumulation and propagation in neurons, the molecular mechanisms underlying 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 lysosomal exocytosis in human dopaminergic neurons, and may represent a potential therapeutic target for Parkinson’s disease and other synucleinopathies. Significant Statement: Parkinson’s disease is the second most common neurodegenerative disease linked to the accumulation of a-synuclein in patient neurons. But it is unclear what this mechanism might be. Here, we demonstrate a novel role for lysosomal exocytosis in clearing intracellular a-synuclein, and show that impairment of this pathway by mutations in the Parkinson’s disease-linked gene ATP13A2/PARK9 contributes to a-synuclein accumulation in human dopaminergic neurons. Importantly, upregulating lysosomal exocytosis by increasing lysosomal Ca2+ levels is sufficient to rescue defective a-synuclein secretion and accumulation in patient neurons. These studies identify lysosomal exocytosis as a potential therapeutic target in diseases characterized by the accumulation of a-synuclein including Parkinson’s disease.
PMID: 31097622 [PubMed – as supplied by publisher]
PMID:
PubMed:31097622
DATE FOUND:
05/18/19 06:00AM
LINK / URL:
https://www.ncbi.nlm.nih.gov/pubmed/31097622?dopt=Abstract