Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice

Abstract

Mutations in the Leucine Rich Repeat Kinase 2 (LRRK2) gene, first described in 2004 have now emerged as the most important genetic finding in both autosomal dominant and sporadic Parkinson's Disease (PD). While a formidable research effort has ensued since the initial gene discovery, little is known of either the normal or the pathological role of LRRK2. We have created lines of mice that express human mutant wild-type (hWT) or G2019S Lrrk2 via bacterial artificial chromosome (BAC) transgenesis. In vivo analysis of the dopaminergic system revealed abnormal dopamine neurotransmission in both hWT and G2019S transgenic mice evidenced by a decrease in extracellular dopamine levels, which was detected without pharmacological manipulation. Immunopathological analysis revealed changes in localization and increased phosphorylation of microtubule binding protein tau in G2019S mice. Quantitative biochemical analysis confirmed the presence of differential phospho-tau species in G2019S mice but surprisingly, upon dephosphorylation the tau isoform banding pattern in G2019S mice remained altered. This suggests that other post-translational modifications of tau occur in G2019S mice. We hypothesize that Lrrk2 may impact on tau processing which subsequently leads to increased phosphorylation. Our models will be useful for further understanding of the mechanistic actions of LRRK2 and future therapeutic screening.

Adult Neurogenesis in Neurodegenerative Diseases: Figure 1.

“…In addition, animals transgenic for LRRK2 containing the most frequent G2019S mutation show increased anxiety-related behavior (Melrose et al 2010). Moreover, LRRK2 is highly expressed in the hippocampus, in particular, in PSA-NCAM expression neuroblasts (Melrose et al 2007).…”

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

“…Two transgenic mouse models overexpressing human G2019S LRRK2 exhibit modest age-dependent DA neuron loss associated with accumulation of autophagosomes and mitochondrial alterations [124,125], but other G2019S LRRK2 transgenic mouse models had diminished dopamine transmission and motor deficits without detectable neuron loss [53,54]. The only I2020T LRRK2 transgenic mouse model reported to date exhibits no obvious loss of DA neurons [126].…”

“…In neurons, G2019S LRRK2 induces shortening of neurite length and, perhaps, alteration of their branching [53,56,57]. I2020T also induces the shortening and debranching of neurites [56,126].…”

“…The physiological function of LRRK2 is unknown, but LRRK2 is involved in autophagy [49,50], vesicle sorting and trafficking [51,52], dopamine homeostasis [53,54], dopamine receptor activation, synaptogenesis [55], and cytoskeleton dynamics (Fig. 2) [56,57].…”

Modeling LRRK2 Parkinsonism

“…While no overt pathological lesions were reported, the authors did reveal that phospho-tau was decreased in the WT transgenic mice. Our group (Melrose et al, 2010) also reported WT and mutant G2019S BAC mice, utilizing a human LRRK2 BAC rather than a murine BAC. Using in vivo microdialysis we demonstrated that basal extracellular dopamine levels were reduced by ~33% in G2019S BAC mice at ~8 months and an enhanced response to amphetamine challenge was noted.…”