Non-Motor and Motor Features in LRRK2 Transgenic Mice

Abstract

BackgroundNon-motor symptoms are increasingly recognized as important features of Parkinson’s disease (PD). LRRK2 mutations are common causes of familial and sporadic PD. Non-motor features have not been yet comprehensively evaluated in LRRK2 transgenic mouse models.ObjectiveUsing a transgenic mouse model overexpressing the R1441G mutation of the human LRRK2 gene, we have investigated the longitudinal correlation between motor and non-motor symptoms and determined if specific non-motor phenotypes precede motor symptoms.MethodologyWe investigated the onset of motor and non-motor phenotypes on the LRRK2R1441G BAC transgenic mice and their littermate controls from 4 to 21 month-old using a battery of behavioral tests. The transgenic mutant mice displayed mild hypokinesia in the open field from 16 months old, with gastrointestinal dysfunctions beginning at 6 months old. Non-motor features such as depression and anxiety-like behaviors, sensorial functions (pain sensitivity and olfaction), and learning and memory abilities in the passive avoidance test were similar in the transgenic animals compared to littermate controls.Conclusions LRRK2R1441G BAC transgenic mice displayed gastrointestinal dysfunction at an early stage but did not have abnormalities in fine behaviors, olfaction, pain sensitivity, mood disorders and learning and memory compared to non-transgenic littermate controls. The observations on olfaction and gastrointestinal dysfunction in this model validate findings in human carriers. These mice did recapitulate mild Parkinsonian motor features at late stages but compensatory mechanisms modulating the progression of PD in these models should be further evaluated.

A novel mitochondrially-targeted apocynin derivative prevents hyposmia and loss of motor function in the leucine-rich repeat kinase 2 (LRRK2R1441G) transgenic mouse model of Parkinson's disease

“…Based on our findings, we conclude that LRRK2 R1441G tg mice may be more suitable for the study of early, non-motor PD-like symptoms (e.g., hyposmia) as opposed to the gross motor defects detected later in PD progression, and that mitochondria-targeted natural product derivative (Mito-apocynin) could be used to prevent early non-motor symptoms. In contrast to the present findings, it was reported in a recent publication that the overexpression of the R1441G mutated form of the human LRRK2 gene did not cause significant change in olfactory function in the transgenic mice compared to non-transgenic control mice [26]. Reasons for this difference are not currently known.…”

Back and to the Future: From Neurotoxin‐Induced to Human Parkinson's Disease Models

“…Several transgenic mouse lines have been created carrying PD‐associated mutations in LRRK2, but none recapitulate the Parkinsonian phenotype observed in human patients (Bichler, Lim, Zeng, & Tan, ; Chen et al., ; Li et al., ; Li et al., ; Ramonet et al., ; Weng et al., ). Bacterial artificial chromosome (BAC) transgenic mice overexpressing human LRRK2‐R1441G at 5 to 10‐fold relative to endogenous levels develop normally, without loss of dopaminergic neuron numbers or striatal dopaminergic innervation.…”

The function of orthologues of the human Parkinson's disease gene LRRK2 across species: implications for disease modelling in preclinical research

“…Bichler et al . saw only subtle motor deficits after the age of 16 months in R1441G mice subjected to open field, rotarod, cylinder, and grip strength tests [122]. Dranka et al .…”

“…Several groups identified signs of altered dopamine neurotransmission [84,105,121,125,128,129], irregular immune response [86,123,124], and/or tau alterations [84,105,121,128]. Gastrointestinal dysfunctions beginning at 6 months of age [122] and olfactory impairment at 15 months of age [123,124] were observed in LRRK2 mice, although not all groups that assessed olfaction ability in LRRK2 mice saw a deficit [122,129]. How these findings may be relevant to human Parkinson’s disease patients is not yet clear; regardless, they could indicate promising new strategies for understanding and targeting disease mechanisms.…”