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Transgenic LRRK2 (R1441G) rats-a model for Parkinson disease?

ABSTRACT: Parkinson disease (PD) is the most common movement disorder, characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra. While the cause of this disease is largely unknown, a rare autosomal dominant familial form of PD is caused by a genetic mutation in the leucine-rich repeat kinase 2 (LRRK2) gene that presumably leads to a gain-of-function of LRRK2 kinase activity. Here, we explored the potential of over expression of this human gene in a new transgenic rat model to serve as an animal model for PD. Commercially available BAC transgenic rats expressing human LRRK2 with the familial PD mutation, R1441G, and their wild-type siblings were tested for deficits in motor function, sensorimotor gating, and higher cognitive function reminiscent of PD through the ages of 3, 6, 9 and 12 months. At 12 months of age, rats were exposed to intraperitoneal injections of the environmental toxin Paraquat or saline. Our results indicate that LRRK2 (R1441G) transgenic rats do not show signs of neurodegeneration and do not develop significant motor or cognitive deficits until the age of 16 months. In addition, LRRK2 (R1441G) transgenic rats did not show increased vulnerability to sub-toxic doses of Paraquat. Gene expression studies indicate that despite genomic presence and initial expression of the transgene, its expression was greatly reduced in our aged rats. We conclude that the transgenic LRRK2 (R1441G) rat is not a valid model for studying the pathology of PD and discuss this in relation to other transgenic rat models.

SUBMITTER: Shaikh KT

PROVIDER: S-EPMC4435452 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Transgenic LRRK2 (R1441G) rats-a model for Parkinson disease?

Shaikh Komal T KT Yang Alvin A Youshin Ekaterina E Schmid Susanne S

PeerJ 20150512

Parkinson disease (PD) is the most common movement disorder, characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra. While the cause of this disease is largely unknown, a rare autosomal dominant familial form of PD is caused by a genetic mutation in the leucine-rich repeat kinase 2 (LRRK2) gene that presumably leads to a gain-of-function of LRRK2 kinase activity. Here, we explored the potential of over expression of this human gene in a new transgenic rat m ...[more]

PMID: 26020005

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Project description:Importance:Few prospective longitudinal studies have evaluated the progression of Parkinson disease (PD) in patients with the leucine-rich repeat kinase 2 (LRRK2 [OMIM 609007]) mutation. Knowledge about such progression will aid clinical trials. Objective:To determine whether the longitudinal course of PD in patients with the LRRK2 mutation differs from the longitudinal course of PD in patients without the mutation. Design, Setting, and Participants:A prospective comprehensive assessment of a large cohort of patients from 3 sites with LRRK2 PD or with nonmutation PD was conducted from July 21, 2009, to September 30, 2016. All patients of Ashkenazi Jewish ancestry with PD were approached at each site; approximately 80% agreed to an initial visit. A total of 545 patients of Ashkenazi Jewish descent with PD who had 1 to 4 study visits were evaluated. A total of 144 patients (26.4%) had the LRRK2 G2019S mutation. Patients with GBA (OMIM 606463) mutations were excluded from the analysis. Main Outcomes and Measures:Linear mixed-effects models for longitudinal motor scores were used to examine the association of LRRK2 mutation status with the rate of change in Unified Parkinson's Disease Rating Scale III scores using disease duration as the time scale, adjusting for sex, site, age, disease duration, cognitive score, and levodopa-equivalent dose at baseline. Mixed-effects models were used to assess change in cognition, as measured by Montreal Cognitive Assessment scores. Results:Among the 545 participants, 233 were women, 312 were men, and the mean (SD) age was 68.2 (9.1) years for participants with the LRRK2 mutation and 67.8 (10.7) years for those without it. Seventy-two of 144 participants with the LRRK2 mutation and 161 of 401 participants with no mutation were women. The estimate (SE) of the rate of change in the Unified Parkinson's Disease Rating Scale III motor score per year among those with the LRRK2 mutation (0.689 [0.192] points per year) was less than among those without the mutation (1.056 [0.187] points per year; difference, -0.367 [0.149] points per year; P = .02). The estimate (SE) of the difference in the rate of change of the Montreal Cognitive Assessment score between those with the LRRK2 mutation (-0.096 [0.090] points per year) and those without the mutation (-0.192 [0.102] points per year) did not reach statistical significance (difference, 0.097 [0.055] points per year; P = .08). Conclusions and Relevance:Prospective longitudinal follow-up of patients with PD with or without the LRRK2 G2019S mutation supports data from a cross-sectional study and demonstrates a slower decline in motor Unified Parkinson's Disease Rating Scale scores among those with LRRK2 G2019S-associated PD.

Project description:BackgroundLeucine-rich repeat kinase 2 (LRRK2) mutation is a common genetic risk factor of Parkinson's disease (PD). Presynaptic dysfunction is an early pathogenic event associated with dopamine (DA) dysregulation in striatum of the brain. DA uptake activity of DA uptake transporter (DAT) affects synaptic plasticity and motor and non-motor behavior. Synaptogyrin-3 (SYNGR3) is part of the synaptogyrin family, especially abundant in brain. Previous in vitro studies demonstrated interaction between SYNGR3 and DAT. Reduced SYNGR3 expression was observed in human PD brains with unclear reasons.MethodsHere, we further explored whether inducing SYNGR3 expression can influence (i) cellular DA uptake using differentiated human SH-SY5Y neuronal cells, (ii) striatal synaptosomal DA uptake in a mutant LRRK2R1441G knockin mouse model of PD, and (iii) innate rodent behavior using the marble burying test.ResultsYoung LRRK2 mutant mice exhibited significantly lower SYNGR3 levels in striatum compared to age-matched wild-type (WT) controls, resembling level in aged WT mice. SYNGR3 is spatially co-localized with DAT at striatal presynaptic terminals, visualized by immuno-gold transmission electron microscopy and immunohistochemistry. Their protein-protein interaction was confirmed by co-immunoprecipitation. Transient overexpression of SYNGR3 in differentiated SH-SY5Y cells increased cellular DA uptake activity without affecting total DAT levels. Inducing SYNGR3 overexpression by adeno-associated virus-7 (AAV7) injection in vivo into striatum increased ex vivo synaptosomal DA uptake in LRRK2 mutant mice and improved their innate marble burying behavior.ConclusionBrain SYNGR3 expression may be an important determinant to striatal DA homeostasis and synaptic function. Our preliminary behavioral test showed improved innate behavior after SYNGR3 overexpression in LRRK2 mutant mice, advocating further studies to determine the influence of SYNGR3 in the pathophysiology of DA neurons in PD.

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Transgenic LRRK2 (R1441G) rats-a model for Parkinson disease?

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Transgenic LRRK2 (R1441G) rats-a model for Parkinson disease?

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