G2019S LRRK2 enhances the neuronal transmission of tau in the mouse brain

Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant Parkinson's disease (PD). LRRK2 mutations typically give rise to Lewy pathology in the brains of PD subjects yet can induce tau-positive neuropathology in some cases. The pathological interaction between LRRK2 and tau remains poorly defined. To explore this interaction in vivo, we crossed a well-characterized human P301S-tau transgenic mouse model of tauopathy with human G2019S-LRRK2 transgenic mice or LRRK2 knockout (KO) mice. We find that endogenous or pathogenic LRRK2 expression has minimal effects on the steady-state levels, solubility and abnormal phosphorylation of human P301S-tau throughout the mouse brain. We next developed a new model of tauopathy by delivering AAV2/6 vectors expressing human P301S-tau to the hippocampal CA1 region of G2019S-LRRK2 transgenic or LRRK2 KO mice. P301S-tau expression induces hippocampal tau pathology and marked degeneration of CA1 pyramidal neurons in mice, however, this occurs independently of endogenous or pathogenic LRRK2 expression. We further developed new AAV2/6 vectors co-expressing human WT-tau and GFP to monitor the neuron-to-neuron transmission of tau within defined hippocampal neuronal circuits. While endogenous LRRK2 is not required for tau transmission, we find that G2019S-LRRK2 markedly enhances the neuron-to-neuron transmission of tau in mice. Our data suggest that mutant tau-induced neuropathology occurs independently of LRRK2 expression in two mouse models of tauopathy but identifies a novel pathogenic role for G2019S-LRRK2 in promoting the neuronal transmission of WT-tau protein. These findings may have important implications for understanding the development of tau neuropathology in LRRK2-linked PD brains.

Cellular and Molecular Basis of Neurodegeneration in Parkinson Disease

“…LRRK2 G2019S mutation elevates mobility of α-synuclein and enhances α-synuclein accumulation in cultured primary neurons and in dopaminergic neurons in SNc of PD brain ( Volpicelli-Daley et al, 2016 ). The mutation also promotes the transmission of Tau in the mouse brain neurons, implicating for understanding the development of tau protein neuropathology in LRRK2-linked PD ( Nguyen et al, 2018 ). Pathogenic mutations in LRRK2 increase its kinase activities in cells and tissues, so small molecule inhibitors of LRRK2 kinase can be used to block its activity to provide neuroprotection in some PD models ( West, 2017 ).…”

What Have We Learned from Cerebrospinal Fluid Studies about Biomarkers for Detecting LRRK2 Parkinson’s Disease Patients and Healthy Subjects with Parkinson’s-Associated LRRK2 Mutations?

“…Even in the atypical parkinsonian disorders that are primary tauopathies, namely CBD and PSP, total and phosphorylated tau concentrations in CSF may not be elevated [174]. (Of relevance with regard to the influence of LRRK2 mutations on tau pathology is that the G2019S LRRK2 mutation has been shown to increase spreading of tau between neurons [175] and to promote tau aggregation and neurotoxicity [176,177]). The four studies comparing ␣-synuclein levels between LRRK2 PD and LRRK2 CTL subjects [78,79,106,109] found no significant pairwise differences.…”

LRRK2 and α-Synuclein: Distinct or Synergistic Players in Parkinson’s Disease?

“…Rab GTPases provide one such link as the G2019S mutation in LRRK2 enhances propagation of α-synuclein in C. elegans through increased phosphorylation of Rab35, and Rab35 plays a central role in a pathway which is essential for tau degradation (Bae et al, 2018;Vaz-Silva et al, 2018). Interestingly, G2019S LRRK2 transgenic mice also show increased neuron-to-neuron tau transmission (Nguyen et al, 2018). Another possible intermediate is GSK-3β, a kinase known to be responsible for the α-synuclein-dependent phosphorylation of tau (Duka et al, 2009).…”