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Investigation of microglial diversity in a LRRK2 G2019S mouse model of Parkinson's disease
L Iovino1, J VanderZwaag2, G Kaur3
1National Research Council (CNR), Institute of Neuroscience, Pisa, Italy; Stella Maris Foundation, IRCCS, Calambrone, Pisa, Italy.
Abstract:
Microglia contribute to the outcomes of various pathological conditions including Parkinson's disease (PD). Microglia are heterogenous, with a variety of states recently identified in aging and neurodegenerative disease models. Here, we delved into the diversity of microglia in a preclinical PD model featuring the G2019S mutation in LRRK2, a known pathological mutation associated with PD. Specifically, we investigated the 'dark microglia' (DM) and the 'disease-associated microglia' (DAM) which present a selective enrichment of CLEC7A expression. In the dorsal striatum - a region affected by PD pathology - extensive ultrastructural features of cellular stress as well as reduced direct cellular contacts, were observed for microglia from old LRRK2 G2019S mice versus controls. In addition, DM were more prevalent while CLEC7A-positive microglia had extensive phagocytic ultrastructural characteristics in the LRRK2 G2019S mice. Furthermore, our findings revealed a higher proportion of DM in LRRK2 G2019S mice, and an increased number of CLEC7A-positive cells with age, exacerbated by the pathological mutation. These CLEC7A-positive cells exhibited a selective enrichment of ameboid morphology and tended to cluster in the affected animals. In summary, we provide novel insights into the occurrence and features of recently defined microglial states, CLEC7A-positive cells and DM, in the context of LRRK2 G2019S PD pathology.
Insights
Parkinson's disease (PD) involves microglia changes. LRRK2 G2019S mutation increases dark microglia (DM) and CLEC7A-positive cells, indicating cellular stress and phagocytic activity in PD models.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Microglia, the brain's immune cells, exhibit diverse states in aging and neurodegeneration.
- Parkinson's disease (PD) is linked to microglial involvement.
- The LRRK2 G2019S mutation is a known risk factor for PD.
Purpose of the Study:
- To investigate microglial heterogeneity in a preclinical PD model with the LRRK2 G2019S mutation.
- To characterize 'dark microglia' (DM) and 'disease-associated microglia' (DAM) expressing CLEC7A.
- To analyze microglial ultrastructural features and cellular contacts in the dorsal striatum.
Main Methods:
- Utilized a preclinical mouse model with the LRRK2 G2019S mutation.
- Performed ultrastructural analysis of microglia in the dorsal striatum.
- Quantified the prevalence of DM and CLEC7A-positive microglia.
- Assessed microglial morphology and cellular clustering.
Main Results:
- Microglia in LRRK2 G2019S mice showed signs of cellular stress and reduced contacts.
- DM were more prevalent, and CLEC7A-positive microglia displayed enhanced phagocytic characteristics.
- The proportion of DM increased with age and was exacerbated by the LRRK2 mutation.
- CLEC7A-positive cells exhibited ameboid morphology and clustered in affected animals.
Conclusions:
- The LRRK2 G2019S mutation influences microglial states, increasing DM and CLEC7A-positive cells.
- These findings provide insights into microglial heterogeneity in PD pathology.
- Specific microglial states are associated with cellular stress and phagocytic activity in the context of LRRK2-linked PD.
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