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J Cell Sci. 2015 Jan 15;128(2):232-8. doi: 10.1242/jcs.164152. Epub 2014 Nov 21.

Dysregulation of lysosomal morphology by pathogenic LRRK2 is corrected by TPC2 inhibition.

Author information

1
Department of Cell and Developmental Biology, University College London, Gower Street, London, WC1E 6BT, UK.
2
Department of Cell Biology, Institute of Ophthalmology, University College London, London, EC1V 9EL, UK.
3
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, 55455, USA.
4
Department of Pharmaceutical Sciences, Thomas Jefferson University, Jefferson School of Pharmacy, Philadelphia, 19107, USA.
5
Department of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, 19140, USA.
6
Department of Clinical Neurosciences, Institute of Neurology, University College London, London, NW3 2PF, UK.
7
Department of Cell and Developmental Biology, University College London, Gower Street, London, WC1E 6BT, UK patel.s@ucl.ac.uk.

Abstract

Two-pore channels (TPCs) are endolysosomal ion channels implicated in Ca(2+) signalling from acidic organelles. The relevance of these ubiquitous proteins for human disease, however, is unclear. Here, we report that lysosomes are enlarged and aggregated in fibroblasts from Parkinson disease patients with the common G2019S mutation in LRRK2. Defects were corrected by molecular silencing of TPC2, pharmacological inhibition of TPC regulators [Rab7, NAADP and PtdIns(3,5)P2] and buffering local Ca(2+) increases. NAADP-evoked Ca(2+) signals were exaggerated in diseased cells. TPC2 is thus a potential drug target within a pathogenic LRRK2 cascade that disrupts Ca(2+)-dependent trafficking in Parkinson disease.

KEYWORDS:

Ca2+; LRRK2; Lysosomes; NAADP; Parkinson disease; TPCN2

PMID:
25416817
PMCID:
PMC4294771
DOI:
10.1242/jcs.164152
[Indexed for MEDLINE]
Free PMC Article

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