BORCS6 is involved in the enlargement of lung lamellar bodies in Lrrk2 knockout mice

Abstract

Leucine-rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinson disease. It has been shown that Lrrk2 knockout (KO) rodents have enlarged lamellar bodies (LBs) in their alveolar epithelial type II cells, although the underlying mechanisms remain unclear. Here we performed proteomic analyses on LBs isolated from Lrrk2 KO mice and found that the LB proteome is substantially different in Lrrk2 KO mice compared with wild-type mice. In Lrrk2 KO LBs, several Rab proteins were increased, and subunit proteins of BLOC-1-related complex (BORC) were decreased. The amount of surfactant protein C was significantly decreased in the bronchoalveolar lavage fluid obtained from Lrrk2 KO mice, suggesting that LB exocytosis is impaired in Lrrk2 KO mice. We also found that the enlargement of LBs is recapitulated in A549 cells upon KO of LRRK2 or by treating cells with LRRK2 inhibitors. Using this model, we show that KO of BORCS6, a BORC subunit gene, but not other BORC genes, causes LB enlargement. Our findings implicate the LRRK2-BORCS6 pathway in the maintenance of LB morphology.

Long-term inhibition of mutant LRRK2 hyper-kinase activity reduced mouse brain α-synuclein oligomers without adverse effects

“…SP-B is a surfactant protein stored in lamellar bodies, which is a useful marker to visualize intracellular pattern of lamellar bodies. Although several reports showed abnormal enlargement of lamellar bodies following LRRK2 inhibition 20 , 80 or after knockout of the Lrrk2 gene 81 , 82 , we did not find any observable differences in both the size and morphology of the lamellar bodies of pneumocytes in our GNE-7915-treated mice compared to the vehicle-treated controls. Although the reason why LRRK2 inhibition causes enlargement of lamellar bodies in these pneumocytes is unclear, the lack of such abnormality in our GNE-7915-treated mice may be attributed to our dosing regimen that did not cause excessive LRRK2 inhibition.…”

Pathogenic LRRK2 compromises the subcellular distribution of lysosomes in a Rab12‐RILPL1‐dependent manner

“…12,14 We have recently shown that LRRK2 plays an important role in the exocytosis of lamellar bodies by regulating the localization of BORCS6, a component of biogenesis of lysosome-related organelles complex 1 (BLOC-1)-related complex (BORC). 15 In macrophages and microglial cells, it has been shown that LRRK2 plays an essential role in alleviating the overloading of lysosomes. 16,17 Furthermore, it has been shown that LRRK2 promotes tubulation of lysosomes by recruiting a motor adaptor protein, c-Jun-amino-terminal kinase-interacting protein 4 (JIP4), thereby facilitating the release of lysosomal membranous contents from cells.…”

“…In addition, Lrrk2 KO mice also show enlarged lamellar bodies, a lysosome‐related organelle, in alveolar epithelial type 2 cells in the lung 12,14 . We have recently shown that LRRK2 plays an important role in the exocytosis of lamellar bodies by regulating the localization of BORCS6, a component of biogenesis of lysosome‐related organelles complex 1 (BLOC‐1)‐related complex (BORC) 15 . In macrophages and microglial cells, it has been shown that LRRK2 plays an essential role in alleviating the overloading of lysosomes 16,17 .…”

The atypical Rab GTPase associated with Parkinson’s disease, Rab29, is localized to membranes

“…A plasmid for bacterial expression encoding an amino-terminally 6His-SUMO1-tagged WT human Rab29 (hRab29/pET-15b-6His-SUMO1; DU50291) and a plasmid for dox-inducible expression in mammalian cells encoding amino-terminally HA-tagged WT human Rab10 (HA-hRab10/pcDNA5D FRT TO; DU44250) were kindly provided by Professor Dario Alessi (University of Dundee) and described previously ( 34 ). Complementary DNA (cDNA) libraries were prepared from human brain total RNA (TaKaRa Bio Inc) using a PrimeScript II 1st strand cDNA synthesis kit with the oligo dT primer (TaKaRa Bio Inc) according to the manufacturer’s instructions.…”