The LRRK2-G2019S mutation attenuates repair of brain injury partially by reducing the release of osteopontin-containing monocytic exosome-like vesicles

Jiawei An; Haijie Yang; Sang Myun Park; Yong-Joon Chwae; Eun-Hye Joe

doi:10.1016/j.nbd.2024.106528

The LRRK2-G2019S mutation attenuates repair of brain injury partially by reducing the release of osteopontin-containing monocytic exosome-like vesicles

Neurobiol Dis. 2024 May 11:197:106528. doi: 10.1016/j.nbd.2024.106528. Online ahead of print.

Authors

Jiawei An¹, Haijie Yang¹, Sang Myun Park¹, Yong-Joon Chwae², Eun-Hye Joe³

Affiliations

¹ Neuroscience Graduate Program, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Kyunggi-do 16499, Republic of Korea; Department of Pharmacology, Ajou University School of Medicine, Suwon, Kyunggi-do 16499, Republic of Korea; Center for Convergence Research of Neurological Disorders, Ajou University School of Medicine, Suwon, Kyunggi-do 16499, Republic of Korea.
² Department of Microbiology, Ajou University School of Medicine, Suwon, Kyunggi-do 16499, Republic of Korea.
³ Neuroscience Graduate Program, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Kyunggi-do 16499, Republic of Korea; Department of Pharmacology, Ajou University School of Medicine, Suwon, Kyunggi-do 16499, Republic of Korea; Center for Convergence Research of Neurological Disorders, Ajou University School of Medicine, Suwon, Kyunggi-do 16499, Republic of Korea. Electronic address: ehjoe@ajou.ac.kr.

PMID: 38740348
DOI: 10.1016/j.nbd.2024.106528

Abstract

Background: Brain injury has been suggested as a risk factor for neurodegenerative diseases. Accordingly, defects in the brain's intrinsic capacity to repair injury may result in the accumulation of damage and a progressive loss of brain function. The G2019S (GS) mutation in LRRK2 (leucine rich repeat kinase 2) is the most prevalent genetic alteration in Parkinson's disease (PD). Here, we sought to investigate how this LRRK2-GS mutation affects repair of the injured brain.

Methods: Brain injury was induced by stereotaxic injection of ATP, a damage-associated molecular pattern (DAMP) component, into the striatum of wild-type (WT) and LRRK2-GS mice. Effects of the LRRK2-GS mutation on brain injury and the recovery from injury were examined by analyzing the molecular and cellular behavior of neurons, astrocytes, and monocytes.

Results: Damaged neurons express osteopontin (OPN), a factor associated with brain repair. Following ATP-induced damage, monocytes entered injured brains, phagocytosing damaged neurons and producing exosome-like vesicles (EVs) containing OPN through activation of the inflammasome and subsequent pyroptosis. Following EV production, neurons and astrocytes processes elongated towards injured cores. In LRRK2-GS mice, OPN expression and monocytic pyroptosis were decreased compared with that in WT mice, resulting in diminished release of OPN-containing EVs and attenuated elongation of neuron and astrocyte processes. In addition, exosomes prepared from injured LRRK2-GS brains induced neurite outgrowth less efficiently than those from injured WT brains.

Conclusions: The LRRK2-GS mutation delays repair of injured brains through reduced expression of OPN and diminished release of OPN-containing EVs from monocytes. These findings suggest that the LRRK2-GS mutation may promote the development of PD by delaying the repair of brain injury.

Keywords: Brain injury; Exosome-like vesicles; LRRK2 G2019S; Monocyte; Neurodegenerative diseases; Osteopontin; Repair.