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Kim C, Beilina A, Smith N, Li Y, Kim M, Kumaran R, Kaganovich A, Mamais A, Adame A, Iba M, Kwon S, Lee WJ, Shin SJ, Rissman RA, You S, Lee SJ, Singleton AB, Cookson MR, Masliah E. LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies. Sci Transl Med. 2020 Oct 14;12(565) PubMed.
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The study by Kim and colleagues sheds light on how α-synuclein released from neurons affects a LRRK2-mediated signaling cascade in microglia to promote neuroinflammation. It has been known for some time that LRRK2 is present in the brain in both neurons and microglia. Research on neuronal LRRK2 has revealed effects of LRRK2 on neuromorphology and membrane trafficking, while research on LRRK2 in microglia showed that LRRK2 expression is upregulated upon immune challenge. It has also been shown that α-synuclein-mediated toxicity is dependent on LRRK2, however, the precise mechanisms for these phenomena had not fully been elucidated.
Kim and colleagues first show that exposing microglia to α-synuclein released from neurons activates LRRK2 within these microglia and leads to the release of neurotoxic molecules from these microglia in a LRRK2 kinase activity-dependent manner. Next, transcriptomics analysis of the α-synuclein-exposed microglia allowed the authors to identify the transcription factor NFATc2 as a key player in the microglial LRRK2 cascade. The authors then found that NFATc2 interacted with and was phosphorylated by LRRK2, and that it translocates to the nucleus in a LRRK2-kinase-dependent manner. The authors also found enhanced activation of NFATc2 in postmortem brain tissue from PD and DLB patients and used the Thy1-α-syn mouse to show that microglial activation and motor deficits can be reversed with a LRRK2 kinase inhibitor.
This study is highly significant in that it integrates events from neurons (synuclein release) with the revelation of key elements of a LRRK2-dependent signaling cascade within microglia and how this contributes to generating a toxic environment for neurons. It also shows how one of the proposed therapeutic strategies for PD, i.e., kinase inhibition of LRRK2, blocks the neurotoxic cascade in microglia and is protective against the development of motor symptoms in a transgenic synucleinopathy mouse model of PD.
Interestingly, the authors point to a limitation of LRRK2 inhibition as they observe that the non-motor symptoms as measured in the open-field test were not rescued but rather exacerbated by the inhibitor treatment. This begs further exploration. Would the same observations be made in other synucleinopathy models, such as the nigral synuclein overexpression models or the prion-like models based on CNS injection of aggregated α-synuclein? Can the effects described above on non-motor phenotypes be further characterized in additional tests beyond the open-field test?
Another obvious thought from reading this paper is how these discoveries might open new opportunities for developing new therapeutic strategies and/or improve existing ones. For instance, for the targeting of LRRK2 itself via a kinase inhibitor, are the primary protective effects coming from LRRK2 inhibition in neurons? In microglia? Or does inhibition in both cell types have an additive effect? Answering this question may help determine how therapeutic effectiveness of LRRK2-based therapies can be improved, for instance by targeting the neuron-specific or microglia-specific LRRK2 signaling cascades.
The neurotoxic cascade in microglia revealed by Kim et al. involves extracellular α-synuclein, TLR2, LRRK2, and NFATc2. It will now be interesting to explore which events in this signaling cascade could be targeted to specifically neutralize neurotoxic effects of microglia in synucleinopathy conditions.
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