Exogenous LRRK2G2019S induces parkinsonian-like pathology in a nonhuman primate

Mestre‐Francés, Nadine; Serratrice, Nicolas; Gennetier, Aurélie; Devau, Gina; Cobo, Sandra; Trouche, Stéphanie; Fontès, Pascaline; Zussy, Charleine; Deurwaerdère, Philippe De; Salinas, Sara; Mennechet, Franck J. D.; Dusonchet, Julien; Schneider, Bernard L.; Saggio, Isabella; Kalatzis, Vasiliki; Luquin-Piudo, M R; Verdier, Jean‐Michel; Kremer, Eric J.

doi:10.1172/jci.insight.98202

Cited by 23 publications

(33 citation statements)

References 63 publications

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“…Furthermore, CAV has been successfully used in a broad diversity of cortical and subcortical projection pathways (Table 1). Even though rodents were used as the animal models in most of CAV applications in Table 1, recently, CAV was also successfully used in non-human primates ( Table 1; Mestre-Francés et al, 2018;Bohlen et al, 2019;Dopeso-Reyes et al, 2019). These studies validate the applicability of CAV as a gene delivery tool in nonhuman primates, facilitating the investigation of neural circuits in a more human-relevant model.…”

Section: Beneficial Properties Of Cav For Circuit Analysismentioning

confidence: 79%

Canine Adenovirus 2: A Natural Choice for Brain Circuit Dissection

Lavoie

Liu

2020

Front. Mol. Neurosci.

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Canine adenovirus-2 (CAV) is a canine pathogen that has been used in a variety of applications, from vaccines against more infectious strains of CAV to treatments for neurological disorders. With recent engineering, CAV has become a natural choice for neuroscientists dissecting the connectivity and function of brain circuits. Specifically, as a reliable genetic vector with minimal immunogenic and cytotoxic reactivity, CAV has been used for the retrograde transduction of various types of projection neurons. Consequently, CAV is particularly useful when studying the anatomy and functions of long-range projections. Moreover, combining CAV with conditional expression and transsynaptic tracing results in the ability to study circuits with cell-and/or projectiontype specificity. Lastly, with the well-documented knowledge of viral transduction, new innovations have been developed to increase the transduction efficiency of CAV and circumvent its tropism, expanding the potential of CAV for circuit analysis.

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Section: Beneficial Properties Of Cav For Circuit Analysismentioning

confidence: 79%

Canine Adenovirus 2: A Natural Choice for Brain Circuit Dissection

Lavoie

Liu

2020

Front. Mol. Neurosci.

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“…In the mouse lemur brain, we also found that it contained the most connected nodes. Given the importance of this network it was critical to characterize it in the mouse lemur, which is widely used as a model of neurodegenerative diseases (Kraska et al, 2011; Mestre-Frances et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…This small animal (typical length 12cm, 60-120g weight) is arboreal and nocturnal. It has a decade-long lifespan and is a model for studying cerebral aging (Sawiak et al, 2014) and various diseases such as diabetes-related encephalopathy (Djelti et al, 2016), Parkinson’s disease (Mestre-Frances et al, 2018), or Alzheimer’s disease (Kraska et al, 2011). It has a key position on phylogenetic trees of primates and is used to investigate primate brain evolution (Montgomery et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Resting state cerebral networks in mouse lemur primates: from multilevel validation to comparison with humans

Garin

Nadkarni

Landeau

et al. 2019

Preprint

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1Measures of resting-state functional connectivity allow the description of neuronal 2 networks in humans and provide a window on brain function in normal and 3 pathological conditions. Animal models are critical to further address experimentally 4 the function of brain networks and their roles in pathologies. Here we describe for the 5 first time brain network organization in the mouse lemur (Microcebus murinus), a 6 small primate attracting increased attention as a model for neuroscience. Resting-7 state functional MR images were recorded at 11.7 Tesla. Forty-eight functional 8 regions were identified and used to identify networks using graph theory, dictionary 9 learning and seed-based analyses. Comparison of results issued from these three 10 complementary methods allowed the description of the most robust networks from 11 mouse lemurs. Large scale networks were then identified from resting-state 12 functional MR images of humans using the same method as for lemurs. Strong 13 homologies were outlined between cerebral networks in mouse lemurs and humans. 14 15 Keywords 16 Brain function, Cerebral networks, Functional MRI, Graph theory, Human, Microcebus 17 murinus, Mouse lemur, Primate, Resting state 18Blood-oxygen level dependent (BOLD) functional magnetic resonance imaging 20 (fMRI) is largely used to investigate brain function in response to specific tasks. In the 21 absence of explicit tasks (i.e. in resting state conditions) patterns of oscillations of the 22 fMRI signal are similar in functionally connected brain structures (Biswal et al., 1995). 23 The detection of the synchronicity of BOLD signal in various brain regions in resting 24 state conditions can thus be used to describe cerebral network organization. In 25 particular this allows the characterization of i. local regions in which highly 26 coordinated neuronal activity occurs and ii. large scale networks composed of 27 widespread functional regions connected together (Biswal et al., 1995; Power et al., 28 2014). 29 Studies of brain networks have contributed to many breakthroughs in the 30 understanding of brain function in normal as well as in pathological conditions such 31 as Alzheimer's or Parkinson's diseases (Buckner et al., 2005; Gao and Wu, 2016). 32 However, many questions remain concerning both the technique and interpretation of 33 resting state fMRI. For example, both the role of resting state networks in cerebral 34 function, and the biological mechanisms underlying their activity, are still partly 35 unknown. Also, how their modulations impact behaviour and cognition in pathological 36 conditions is still debated (Mohan et al., 2016). 37Using animal models is critical to further address these questions. Indeed, in 38 animals it is possible to artificially stimulate neuronal activity to characterize biological 39 mechanisms underlying network function (Gerits et al., 2012). Another interest of 40 studying neuronal networks in animals is to evaluate how evolution has driven 41 network architecture and to assess to wha...

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“…A similar study using broadlyexpressing Ad5-LRRK2 vectors in mouse brain compared G2019S and another kinase-inactive mutation, D1994A LRRK2, revealing neuroinflammation and vacuolization in aged mice due to LRRK2 expression in glial cells (48). A recent study in the non-human primate, Microcebus murinus, using long-acting canine adenovirus type 2 vectors, revealed an equivalent level of neuronal loss induced by WT and G2019S LRRK2 but without evaluating kinase activity (49). Therefore, the contribution of kinase activity in these or any mutant LRRK2 animal model has not been clearly established.…”

Section: G2019s Mutation In Vivomentioning

confidence: 94%

Dopaminergic Neurodegeneration Induced by Parkinson’s Disease-Linked G2019S LRRK2 is Dependent on Kinase and GTPase Activity

Nguyen

Tsika

Kelly

et al. 2019

Preprint

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Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant familial Parkinson's disease (PD) and represent the most common known cause of PD. LRRK2 can function as both a protein kinase and GTPase and PDlinked mutations are known to influence both of these enzymatic activities. While PD-linked LRRK2 mutations can commonly induce neuronal damage and toxicity in cellular models, the mechanisms underlying these pathogenic effects remain uncertain.Rodent models based upon familial LRRK2 mutations often lack the hallmark features of PD and robust neurodegenerative phenotypes in general. Here, we develop a robust pre-clinical model of PD in adult rats induced by the brain delivery of recombinant adenoviral vectors with neuronal-specific expression of full-length human LRRK2 harboring the most common G2019S mutation. In this model, G2019S LRRK2 induces the robust degeneration of substantia nigra dopaminergic neurons, a pathological hallmark of PD. Introduction of a stable kinase-inactive mutation or in-diet dosing with the selective kinase inhibitor, PF-360, attenuates neurodegeneration induced by G2019S LRRK2. Neuroprotection provided by pharmacological kinase inhibition is mediated by an unusual mechanism involving the selective and robust destabilization of human LRRK2 protein in the rat brain relative to endogenous LRRK2. Our study further demonstrates that dopaminergic neurodegeneration induced by G2019S LRRK2 critically requires normal GTPase activity. The introduction of hypothesis-testing mutations that increase GTP hydrolysis or impair GTP binding activity provide neuroprotection against G2019S LRRK2 via distinct mechanisms. Taken together, our data demonstrate that G2019S LRRK2 induces neurodegeneration in vivo via a mechanism that is dependent on kinase and GTPase activity. Our study provides a robust rodent model of LRRK2-linked PD and nominates kinase inhibition and modulation of GTPase activity as promising disease-modifying therapeutic targets.

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Exogenous LRRK2G2019S induces parkinsonian-like pathology in a nonhuman primate

Cited by 23 publications

References 63 publications

Canine Adenovirus 2: A Natural Choice for Brain Circuit Dissection

Canine Adenovirus 2: A Natural Choice for Brain Circuit Dissection

Resting state cerebral networks in mouse lemur primates: from multilevel validation to comparison with humans

Dopaminergic Neurodegeneration Induced by Parkinson’s Disease-Linked G2019S LRRK2 is Dependent on Kinase and GTPase Activity

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