Pathologic α-Synuclein Species Activate LRRK2 in Pro-Inflammatory Monocyte and Macrophage Responses
Xu, E.; Boddu, R.; Abdelmotilib, H. A.; Kelly, K.; Sokratian, A.; Harms, A. S.; Schonhoff, A. M.; Bryant, N.; Harmsen, I. E.; Schlossmacher, M.; Chandra, S.; Krendelshchikova, V.; Liu, Z.; West, A. B.
Show abstract
Missense mutations in the LRRK2 gene that lead to LRRK2 kinase hyperactivity can cause Parkinsons disease (PD). The link between LRRK2 and -synuclein aggregation in PD remains enigmatic. Numerous reports suggest critical LRRK2 functions in microglial responses. Herein, we find that LRRK2-positive immune cells in the brain represent CD68-positive pro-inflammatory, monocyte-derived macrophages, distinct from microglia. Rod -synuclein fibrils stimulate LRRK2 kinase activity in monocyte-derived macrophages, and LRRK2 mutations lead to enhanced recruitment of classical monocytes into the midbrain in response to -synuclein. LRRK2 kinase inhibition blocks -synuclein fibril induction of LRRK2 protein in both human and murine macrophages, with human cells demonstrating much higher LRRK2 levels and kinase activity than equivalent murine cells. Further, interferon-{gamma} strongly induces LRRK2 kinase activity in primary human macrophages in comparison to weak effects observed in murine cells. These results highlight peripheral immune responses in LRRK2-linked paradigms that further connect two central proteins in PD.
Matching journals
The top 8 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice 96%
- Cystatin F (Cst7) drives sex-dependent changes in microglia in an amyloid-driven model of Alzheimer's Disease 96%
- Prions induce minor genome-wide translational changes in neurons compared to glia 96%
Similar papers in this journal
- A versatile mouse model to advance human microglia transplantation research in neurodegenerative diseases 96%
- TREM2-H157Y Increases Soluble TREM2 Production and Reduces Amyloid Pathology 96%
- A Trem2*R47H mouse model without cryptic splicing drives age- and disease-dependent tissue damage and synaptic loss in response to plaques 96%
Similar papers in this journal
Similar papers in this journal
- Conserved and cell type-specific transcriptional responses to IFN-γ in the ventral midbrain 96%
- A Novel Tmem119-tdTomato Reporter Mouse Model for Studying Microglia in the Central Nervous System 95%
- Transcriptomic and functional analysis of Aβ1-42 oligomer-stimulated human monocyte-derived microglia-like cells 95%
Similar papers in this journal
- Neuropathology in an α-synuclein preformed fibril mouse model occurs independent of the Parkinson's disease-linked lysosomal ATP13A2 protein 96%
- Extracellular tau clearance is governed by its aggregation state and independent of microglial activation by LPS and IFN-γ 95%
- A double-hit in vivo model of GBA1 viral microRNA-mediated downregulation and human alpha-synuclein overexpression demonstrates nigrostriatal degeneration 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.