Abstract
Backgroundα-Synuclein (αSYN) has been genetically implicated in familial and sporadic Parkinson’s disease (PD), and is associated with disease susceptibility, progression and pathology. Excess amounts of αSYN are toxic to neurons. In the brain, microglial αSYN clearance is closely related to neuronal survival. Leucine-rich repeat kinase 2 (LRRK2) is the one of the other genes implicated in familial and sporadic PD. While LRRK2 is known to be expressed in microglia, its true function remains to be elucidated. In this study, we investigated αSYN clearance by microglia isolated from LRRK2-knockout (KO) mice.ResultsIn LRRK2-KO microglia, αSYN was taken up in larger amounts and cleared from the supernatant more effectively than for microglia isolated from wild-type (WT) mice. This higher clearance ability of LRRK2-KO microglia was thought to be due to an increase of Rab5-positive endosomes, but not Rab7- or Rab11-positive endosomes. Increased engagement between Rab5 and dynamin 1 was also observed in LRRK2-KO microglia.ConclusionLRRK2 negatively regulates the clearance of αSYN accompanied by down-regulation of the endocytosis pathway. Our findings reveal a new functional role of LRRK2 in microglia and offer a new insight into the mechanism of PD pathogenesis.
Highlights
Background αSynuclein is one of the key molecules involved in familial and sporadic Parkinson’s disease (PD) [1,2,3,4,5]; genomic multiplication and point mutations in the α-synuclein gene (SNCA) are known to be causal factors for the familial parkinsonism forms of PD, PARK1 and PARK4 [6,7,8,9]. αSYN comprises 140 amino acids, which form an amphipathic region, a NAC domain, and an acidic tail [10]
Leucine-rich repeat kinase 2 (LRRK2) is a negative regulator of αSYN clearance in microglia To investigate the function of microglial LRRK2, primary microglia were prepared from LRRK2-KO mice and littermate WT control mice by Ni’s method [49]
The phagocytotic activities of KO and WT microglia did not differ from each other when analyzed using fluorescent latex beads (Fig. 1c). These results indicated that LRRK2 is not related to these microglial phenotypes
Summary
Background αSynuclein (αSYN; SNCA) is one of the key molecules involved in familial and sporadic Parkinson’s disease (PD) [1,2,3,4,5]; genomic multiplication and point mutations in the α-synuclein gene (SNCA) are known to be causal factors for the familial parkinsonism forms of PD, PARK1 and PARK4 [6,7,8,9]. αSYN comprises 140 amino acids, which form an amphipathic region, a NAC domain, and an acidic tail [10]. ΑSYN is expressed in Microglia are immune cells in the brain playing crucial roles in inflammatory responses, scavenging, and production of neurotropic factors [19]. In Alzheimer’s disease, β-amyloid stimulates microglia and induces the production of inflammatory cytokines [22]. Clearance of β-amyloid by microglia has a critical role in prevention of the disease [23, 24]. In PD, microglia are involved in both disease -prevention through clearance of αSYN and disease -progression through production of inflammatory cytokines in which the oligomeric αSYN stimulates toll-like receptor (TLR) 2 whereas a high amount of monomeric αSYN stimulates TLR4 [25,26,27,28]
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