TransgenicLRRK2^R1441Grats–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 LRRK2R1441G 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, LRRK2R1441G 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 LRRK2R1441G rat is not a valid model for studying the pathology of PD and discuss this in relation to other transgenic rat models.

Progress in LRRK2-Associated Parkinson’s Disease Animal Models

“…Importantly, all residues affected by pathogenic mutations in humans are conserved in rodent LRRK2 (Langston et al, 2016). Rodents also possess a LRRK1 homolog, which shares ankyrin repeats (ANK), leucine-rich repeats (LRR), and Roc, COR, and kinase domains with LRRK2, but may also contain a WD40 domain that is still contested in the literature (Biskup et al, 2007;Civiero et al, 2012;Sejwal et al, 2017;Xing et al, 2017). The dopaminergic neuroanatomical pathways of rodents and humans are also highly similar, leading to the development of an array of sensitive behavioral tests in rodents that may correlate to dopamine loss in human PD (Meredith and Kang, 2006;Redgrave et al, 2010).…”

Current and Emerging MR Methods and Outcome in Rodent Models of Parkinson’s Disease: A Review

“…Transgenic mice present little to no DA neurodegeneration; however, most of them have abnormalities in the nigrostriatal system, α-synuclein aggregation, or impaired DA release ( Li et al, 2009 ; Jagmag et al, 2016 ). Likewise, LRRK2 mutated rats do not show any DA neurodegeneration in the SN but rather behavioral alterations ( Daher et al, 2014 ; Walker et al, 2014 ; Lee et al, 2015 ; Shaikh et al, 2015 ; Sloan et al, 2016 ).…”

New Developments in Genetic rat models of Parkinson's Disease

“…These studies highlight the utility of LRRK2‐KO rats for PD research, even though these rats do not have PD‐related phenotypes . Several lines of transgenic rats expressing human wild‐type LRRK2 or LRRK2 with the PD‐linked point mutant G2019S, R1441C, or R1441G have been characterized . Similar to mice, no LRRK2 transgenic rats show significant loss of nigral dopaminergic neurons.…”