The G2019S LRRK2 mutation exacerbates α-synuclein and tau neuropathology through divergent pathways in Parkinson’s disease models

Nov 11, 2025Acta neuropathologica

The G2019S LRRK2 mutation worsens alpha-synuclein and tau brain damage through different processes in Parkinson’s disease models

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Abstract

Viral vector-mediated α-synuclein overexpression in GS LRRK2 knock-in mice led to enhanced dopaminergic neurodegeneration and increased phosphorylated α-synuclein levels.

Aggregated α-synuclein and are both observed in Parkinson's disease brains, suggesting multiple proteinopathies may coexist.
Mutations in the LRRK2 gene, particularly G2019S, are the most common cause of familial Parkinson's disease.
Overexpression of α-synuclein in LRRK2 mutant mice resulted in pronounced neuroinflammation and impaired clearance of α-synuclein.
Human neurons derived from G2019S LRRK2 patients exhibited similar pathological features as observed in the mouse model.
Tau overexpression in the same mouse model increased tau phosphorylation but did not significantly affect inflammation or neurodegeneration, indicating a different mechanism.

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Aggregated α-synuclein (αSyn) is a pathological hallmark of Parkinson's disease (PD), yet other protein aggregates, including , are commonly observed in PD brains. This suggests that PD is not solely a synucleinopathy but may involve multiple, coexisting proteinopathies. Mutations in LRRK2, particularly the G2019S (GS), are the most common cause of familial PD. LRRK2-PD has been associated with both αSyn and tau pathology; however the mechanistic links between LRRK2 dysfunction and protein aggregation remain incompletely defined. Here we opted to investigate whether LRRK2 contributes to αSyn and tau pathology through common molecular pathways or via distinct cellular mechanisms. Viral vector-mediated αSyn overexpression in GS LRRK2 knock-in mice led to enhanced dopaminergic neurodegeneration, increased phosphorylated αSyn levels, pronounced neuroinflammation, and accumulation of lysosomal proteins, suggesting impaired αSyn clearance and immune activation as key drivers. Human iPSC-derived dopaminergic neurons from GS LRRK2 PD patients mirrored these findings. In contrast viral vector-mediated overexpression of tau in GS LRRK2 knock-in mice promoted tau phosphorylation but did not significantly affect neuroinflammation, lysosomal markers, or neurodegeneration, indicating a primarily cell-autonomous mechanism. Our results reveal a mechanistic divergence in how GS LRRK2 impacts αSyn and tau pathologies, supporting the notion that LRRK2 kinase activity contributes to PD pathogenesis through different pathways, thereby highlighting its potential as a therapeutic target in both familial and sporadic PD.

Key numbers

significantly higher

Increase in dopaminergic neuron loss

Loss of + neurons in GS LRRK2 mice post αSyn overexpression

higher levels of IL-33, CCL2, CCL3, CXCL10, IFN-γ, IL-10, IL-1β, IL-2, and TNF-α

Increased cytokine levels

Cytokines measured in protein extracts from GS LRRK2 mice after αSyn injection

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The G2019S LRRK2 mutation exacerbates α-synuclein and tau neuropathology through divergent pathways in Parkinson’s disease models

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