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

Author:

Araki Miho1ORCID,Ito Kyohei1ORCID,Takatori Sho1ORCID,Ito Genta2ORCID,Tomita Taisuke12ORCID

Affiliation:

1. Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan

2. Social Cooperation Program of Brain and Neurological Disorders, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan

Abstract

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.

Funder

Mitsubishi Foundation

GSK

Japan Society for the Promotion of Science

Exploratory Research for Advanced Technology

Grants-in-Aid for Scientific Research

Publisher

Oxford University Press (OUP)

Subject

Genetics (clinical),Genetics,Molecular Biology,General Medicine

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