LRRK2-mediated neuroinflammation induced neuronal dysfunctions in a Parkinson's and Alzheimer's disease cellular model
Year: 2025
Type: article
Abstract: Chronic neuroinflammation plays a crucial role in the progression of several neurodegenerative diseases (NDs), including Parkinson's disease (PD) and Alzheimer's disease (AD). Interestingly, Leucine-Rich Repeat Kinase 2 (LRRK2), a gene linked to familial and sporadic cases of PD, has been widely associated to the neuroinflammatory response. To date, it is well-established that LRRK2 kinase activity is a positive regulator of neuroinflammation both in in vitro and in in vivo systems. Taken together, these observations suggest that LRRK2 might actively contribute to neuronal damage and degeneration in NDs. Based on these premises, in this study we explored the impact of LRRK2-mediated neuroinflammation on neurons in a PD- and AD-related context. We set-up a cellular model composed by hiPSC-derived neurons (dopaminergic neurons for PD and cholinergic neurons for AD) exposed to inflamed glial medium (a-synuclein pffs-mediated inflammation for PD and Ab fibrils-mediated inflammation for AD) for several days. In the attempt to dissect the effect of neuroinflammation, and specifically the role of LRRK2, on neuronal functions we first performed transcriptome differential analysis and then we validated the results at functional levels. Remarkably, we found that LRRK2-dependent neuroinflammation contributes to neuronal dysfunctions and death in both NDs and that LRRK2 kinase inhibition prevents these detrimental effects. Overall, our results suggest that lowering neuroinflammation through pharmacologic inhibition of LRRK2 might limit the progression of NDs and thus be neuroprotective.
Author: Russo, Isabella
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W6949474207
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