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Dysregulation of lysosomal morphology by pathogenic LRRK2 is corrected by TPC2 inhibition. J Cell Sci 2015 Jan 15;128(2):232-8

Date

11/25/2014

Pubmed ID

25416817

Pubmed Central ID

PMC4294771

DOI

10.1242/jcs.164152

Scopus ID

2-s2.0-84921415558   87 Citations

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.

Author List

Hockey LN, Kilpatrick BS, Eden ER, Lin-Moshier Y, Brailoiu GC, Brailoiu E, Futter CE, Schapira AH, Marchant JS, Patel S

Author

Jonathan S. Marchant PhD Chair, Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Calcium
Calcium Channels
Calcium Signaling
Fibroblasts
HEK293 Cells
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Lysosomes
NADP
Parkinson Disease
Primary Cell Culture
Protein-Serine-Threonine Kinases
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a