Alterations in late endocytic trafficking related to the pathobiology of LRRK2-linked Parkinson's disease. Biochem Soc Trans 2015 Jun;43(3):390-5
Date
05/27/2015Pubmed ID
26009181DOI
10.1042/BST20140301Scopus ID
2-s2.0-84934967144 (requires institutional sign-in at Scopus site) 26 CitationsAbstract
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene comprise the most common cause of familial Parkinson's disease (PD), and variants increase the risk for sporadic PD. LRRK2 displays kinase and GTPase activity, and altered catalytic activity correlates with neurotoxicity, making LRRK2 a promising therapeutic target. Despite the importance of LRRK2 for disease pathogenesis, its normal cellular function, and the mechanism(s) by which pathogenic mutations cause neurodegeneration remain unclear. LRRK2 seems to regulate a variety of intracellular vesicular trafficking events to and from the late endosome in a manner dependent on various Rab proteins. At least some of those events are further regulated by LRRK2 in a manner dependent on two-pore channels (TPCs). TPCs are ionic channels localized to distinct endosomal structures and can cause localized calcium release from those acidic stores, with downstream effects on vesicular trafficking. Here, we review current knowledge about the link between LRRK2, TPC- and Rab-mediated vesicular trafficking to and from the late endosome, highlighting a possible cross-talk between endolysosomal calcium stores and Rab proteins underlying pathomechanism(s) in LRRK2-related PD.
Author List
Rivero-Ríos P, Gómez-Suaga P, Fernández B, Madero-Pérez J, Schwab AJ, Ebert AD, Hilfiker SAuthor
Allison D. Ebert PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Calcium ChannelsEndocytosis
Endosomes
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Lysosomes
Mutation
Nerve Degeneration
Parkinson Disease
Protein Transport
RNA-Binding Proteins
