Li Y, Liu W, Oo TF, Wang L, Tang Y, Jackson-Lewis V, Zhou C, Geghman K, Bogdanov M, Przedborski S, Beal MF, Burke RE, Li C. Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson's disease. Nat Neurosci. 2009 Jul;12(7):826-8. PubMed.
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National Institute on Aging
A progressive, and eventually dramatic, depletion of dopamine-containing neurons that project from the substantia nigra pars compacta to the striatum is one hallmark of Parkinson disease. Nigral cell loss is thought to be the pathological event leading to many of the movement problems in PD and is the basis of mainstay therapy using L-DOPA for many patients. Several toxins, including 6-OHDA, MPTP and rotenone, have been used for several years to induce dramatic damage to the substantia nigra as a model of parkinsonism (1). Although there are some problems with these models, they have been very important in understanding mechanisms related to denervation in the basal ganglia. In contrast, genetic-based models have produced generally mild and sometimes inconsistent phenotypes (2). Furthermore, none that I know of produce a dramatic lesion of the nigra or a particularly strong behavioral output. Delivery of α-synuclein, a gene thought to be causal for PD, directly to the substantia nigra using viral vectors produces the most striking cell loss phenotype (3) but even this is incomplete. One can argue how critical it is to have this specific phenotype, especially as we know that PD involves many different brain regions, but most would acknowledge that an L-DOPA responsive phenotype based on nigral cell loss would at least be a preferred effect of genetic manipulation.
Into this history comes the genetically modified mouse from the Cornell group (4) showing a dramatic phenotype of very slow spontaneous movement. The LRRK2 R1441G mutation used here was first found in a series of families from the Basque region of Northern Spain (5) and is definitively pathogenic. There are several important aspects to this paper by Li et al; first, it supports the contention that mutant LRRK2 can be toxic in vivo as previously suggested in cell models; second, a strong and age-related behavioral effect is seen in the presence of moderate cell loss and axonal damage; third, the behavioral output is rescued by L-DOPA, suggesting a possible overlap with mechanisms seen in human PD patients. Although not always compared side-by-side, mice overexpressing wild-type LRRK2 do not show any of these effects (4).
Given the strong effects, it is strongly hoped that other researchers are able to access these or similar mouse models and this is apparently in place (6). Comparison with other pathogenic mutations is a critical next step, as is the important requirement to show that phenotypes are stable across multiple generations of this line, which would make them very useful. One surprise that needs to be resolved is where the behavioral phenotype is localized anatomically. Returning to the point about toxin models, in 6-OHDA lesions a very substantive loss of nigral projections can be achieved (up to 90 percent in some paradigms) without necessarily inducing the same level of akinetic behavior. This might indicate that other brain circuits are involved. One might propose that the striatal target cells are also damaged in this model; this seems highly unlikely given that L-DOPA is effective, and this drug is thought to require an intact striatum to work. Excitingly, the Li et al. mice now give us a platform where such experiments can feasibly be performed.
See also:
PD Online Research
References:
Terzioglu M, Galter D. Parkinson's disease: genetic versus toxin-induced rodent models. FEBS J. 2008 Apr;275(7):1384-91. PubMed.
Chesselet MF, Fleming S, Mortazavi F, Meurers B. Strengths and limitations of genetic mouse models of Parkinson's disease. Parkinsonism Relat Disord. 2008;14 Suppl 2:S84-7. PubMed.
Schneider B, Zufferey R, Aebischer P. Viral vectors, animal models and new therapies for Parkinson's disease. Parkinsonism Relat Disord. 2008;14 Suppl 2:S169-71. Epub 2008 Jun 27 PubMed.
Li Y, Liu W, Oo TF, Wang L, Tang Y, Jackson-Lewis V, Zhou C, Geghman K, Bogdanov M, Przedborski S, Beal MF, Burke RE, Li C. Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson's disease. Nat Neurosci. 2009 Jul;12(7):826-8. PubMed.
Paisán-Ruíz C, Jain S, Evans EW, Gilks WP, Simón J, van der Brug M, López de Munain A, Aparicio S, Gil AM, Khan N, Johnson J, Martinez JR, Nicholl D, Carrera IM, Pena AS, de Silva R, Lees A, Martí-Massó JF, Pérez-Tur J, Wood NW, Singleton AB. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron. 2004 Nov 18;44(4) PubMed.
View all comments by Mark CooksonBoston University School of Medicine
LRRK2 R1441C Mice Recapitulate PD Motor Deficits
The recent article by C.J. Li’s group reports on the first transgenic LRRK2 mouse model. The LRRK2 mouse uses a BAC system to express WT or R1441C LRRK2, which is a mutation in the GTPase domain of LRRK2. The benefit of the BAC system is that it permits use of the LRRK2 promoter, which allows for an expression pattern that is elevated but exhibits a distribution that recapitulates the pattern of endogenous LRRK2. The mouse is notable in several respects. The most important observation is that the mouse exhibits age-dependent motor deficits that are responsive to L-DOPA, which is a classic phenotype observed in patients with Parkinson disease and shows that the motor deficits derive from dysfunction of dopaminergic neurons. The nature of the dysfunction, though, is not entirely clear. The group reports a modest decrease in dopamine release from the neurons. This phenotype is reminiscent of phenotypes observed for parkin and PINK1 mice, and might be a preliminary indication that deficits in dopamine release are a common feature of genes associated with PD. A second encouraging observation is that mice show signs that are commonly associated with neuronal degeneration. The researchers observe tyrosine hydroxylase positive spheroids, and increased tau phosphorylation, shown with the AT8 antibody.
These degenerative phenotypes are interesting for what they do and do not show. On the positive side, the morphologic changes are consistent with a hypothesis that there is degeneration of dopaminergic neurons. Spheroids are a common, non-specific sign of neurodegeneration. Tau phosphorylation is also an early sign of neuronal degeneration, or at least neuronal stress. From my perspective, the evidence of dopaminergic degeneration is quite believable because it is consistent with what we observe in our C. elegans model, which has been in review for over a year and hopefully will be out soon. The presence of phospho-tau reactivity is also interesting because neurofibrillary tangles are observed in some cases of LRRK2-associated parkinsonism, and because polymorphisms in tau are strongly associated with Parkinson disease, being the second strongest result observed in multiple GWAS studies after those in α-synuclein. On the negative side, the manuscript is striking for the absence of any mention of loss of dopamine neurons or the presence of α-synuclein inclusions or Lewy body pathology. This might mean that expressing mutant LRRK2 alone is insufficient to recapitulate Parkinson disease and one needs to also have the human proteins present, such as α-synuclein and tau. Alternatively, this might reflect the vagaries of transgenic models, and some other models might show α-synuclein pathology (although I am not aware of any reports of α-synuclein pathology in the other mouse models that are in development). Nevertheless, the presence of a L-DOPA responsive transgenic mouse model derived from a genetic mutation associated with Parkinson disease represents an important advance for the field.
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