Animal models of α-synucleinopathy for Parkinson disease drug development

Koprich, James B.; Kalia, Lorraine V.; Brotchie, Jonathan M.

doi:10.1038/nrn.2017.75

Cited by 182 publications

(182 citation statements)

References 209 publications

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“…This expression of α-syn results in abnormal α-syn (p-Ser129+), inflammation, and subsequent neurodegeneration 6 months post transduction [14, 16, 27]. It is important to consider caveats of this model which include the need for surgical injection of the virus and induction of a high level of α-syn expression, but it does model many of the features observed in human PD [33, 34]. The α-syn expression, inflammation, and neurodegeneration in this model have been thoroughly characterized and are reproducible [14–16, 27–29].…”

Section: Discussionmentioning

confidence: 99%

Targeting of the class II transactivator attenuates inflammation and neurodegeneration in an alpha-synuclein model of Parkinson’s disease

Williams

Schonhoff

Jurkuvenaite

et al. 2018

J Neuroinflammation

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BackgroundParkinson’s disease (PD) is characterized by intracellular alpha-synuclein (α-syn) inclusions, progressive death of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and activation of the innate and adaptive immune systems. Disruption of immune signaling between the central nervous system (CNS) and periphery, such as through targeting the chemokine receptor type 2 (CCR2) or the major histocompatibility complex II (MHCII), is neuroprotective in rodent models of PD, suggesting a key role for innate and adaptive immunity in disease progression. The purpose of this study was to investigate whether genetic knockout or RNA silencing of the class II transactivator (CIITA), a transcriptional co-activator required for MHCII induction, is effective in reducing the neuroinflammation and neurodegeneration observed in an α-syn mouse model of PD.MethodsIn vitro, we utilized microglia cultures from WT or CIITA −/− mice treated with α-syn fibrils to investigate inflammatory iNOS expression and antigen processing via immunocytochemistry (ICC). In vivo, an adeno-associated virus (AAV) was used to overexpress α-syn in WT and CIITA −/− mice as a model for PD. Concurrently with AAV-mediated overexpression of α-syn, WT mice received CIITA-targeted shRNAs packaged in lentiviral constructs. Immunohistochemistry and flow cytometry were used to assess inflammation and peripheral cell infiltration at 4 weeks post transduction, and unbiased stereology was used 6 months post transduction to assess neurodegeneration.ResultsUsing ICC and DQ-ovalbumin, we show that CIITA −/− microglial cultures failed to upregulate iNOS and MHCII expression, and had decreased antigen processing in response to α-syn fibrils when compared to WT microglia. In vivo, global knock-out of CIITA as well as local knockdown using lentiviral shRNAs targeting CIITA attenuated MHCII expression, peripheral immune cell infiltration, and α-syn-induced neurodegeneration.ConclusionOur data provide evidence that CIITA is required for α-syn-induced MHCII induction and subsequent infiltration of peripheral immune cells in an α-syn mouse model of PD. Additionally, we demonstrate that CIITA in the CNS drives neuroinflammation and neurodegeneration. These data provide further support that the disruption or modulation of antigen processing and presentation via CIITA is a promising target for therapeutic development in preclinical animal models of PD.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1286-2) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Targeting of the class II transactivator attenuates inflammation and neurodegeneration in an alpha-synuclein model of Parkinson’s disease

Williams

Schonhoff

Jurkuvenaite

et al. 2018

J Neuroinflammation

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“…Furthermore, this phenomenon has been recapitulated in a variety of laboratory animals including mice, rats, and nonhuman primates (e.g., macaque, marmoset) [27, 33, 34]. These models thus provide a versatile platform for studying the basic mechanisms associated with transmission as well as for evaluating therapeutics directed against PD processes which have been reviewed elsewhere [35–37]. …”

Section: Introductionmentioning

confidence: 99%

Stereotaxic Targeting of Alpha-Synuclein Pathology in Mouse Brain Using Preformed Fibrils

Zhang

Kehm

Gathagan

et al. 2019

Methods in Molecular Biology

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The accumulation of intraneuronal inclusions containing misfolded alpha-synuclein (aSyn) within the central nervous system (CNS) is a common feature found in several neurodegenerative disorders including Parkinson’s disease (PD). Emerging evidence indicates that aSyn amyloid fibrils, a configuration that is present within these characteristic inclusions, are capable of self-replicating by templating the conversion of endogenously expressed aSyn in neurons. Stereotaxic administration of synthetic α-synuclein preformed fibrils (PFFs) into the mouse brain has been shown to seed the formation of intracellular aSyn pathology reminiscent of Lewy body (LB) inclusions present in human PD and related synucleinopathies. Moreover, pathology can be targeted to specific CNS regions. This experimental approach provides a versatile platform for investigating PD-like LB pathology in vivo. We focus here on procedures for initiating aSyn inclusion formation at various regions of the mouse brain using computer-assisted motorized stereotaxic microinjection of aSyn PFFs and discuss appropriate strategies for controls and analysis.

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“…α‐Synuclein is abundantly expressed in brain and localizes predominately to presynaptic terminals of neurons, where it facilitates the exocytosis of synaptic vesicles . Because α‐synuclein mutations are dominantly inherited, and because duplication and triplication mutations of the wild‐type human SNCA gene are also causally linked to PD, many laboratories have generated mice and rats overexpressing wild‐type and mutant α‐synuclein to generate PD animal models . Surprisingly, most lines of transgenic mice overexpressing wild‐type or mutant α‐synuclein fail to develop significant loss of dopaminergic neurons in the substantia nigra or significant synuclein‐immunoreactive pathology similar to Lewy bodies, which are the hallmarks of PD.…”

Section: Genetic Rat Models Of Pdmentioning

confidence: 99%

“…We focus this review on genetic rat models of PD, including rats injected with proteins or virally expressed genes with mutations linked to PD. Mouse and neurotoxin animal models of PD remain important research tools, described in more detail by many comprehensive and focused reviews …”

mentioning

confidence: 99%

New Developments in Genetic rat models of Parkinson's Disease

Creed

Goldberg

2018

Movement Disorders

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Preclinical research on Parkinson's disease has relied heavily on mouse and rat animal models. Initially, PD animal models were generated primarily by chemical neurotoxins that induce acute loss of dopaminergic neurons in the substantia nigra. On the discovery of genetic mutations causally linked to PD, mice were used more than rats to generate laboratory animals bearing PD-linked mutations because mutagenesis was more difficult in rats. Recent advances in technology for mammalian genome engineering and optimization of viral expression vectors have increased the use of genetic rat models of PD. Emerging research tools include "knockout" rats with disruption of genes in which mutations have been causally linked to PD, including LRRK2, α-synuclein, Parkin, PINK1, and DJ-1. Rats have also been increasingly used for transgenic and viral-mediated overexpression of genes relevant to PD, particularly α-synuclein. It may not be realistic to obtain a single animal model that completely reproduces every feature of a human disease as complex as PD. Nevertheless, compared with mice with the same mutations, many genetic rat animal models of PD better reproduce key aspects of PD including progressive loss of dopaminergic neurons in the substantia nigra, locomotor behavior deficits, and age-dependent formation of abnormal α-synuclein protein aggregates. Here we briefly review new developments in genetic rat models of PD that may have greater potential for identifying underlying mechanisms, for discovering novel therapeutic targets, and for developing greatly needed treatments to slow or halt disease progression. © 2018 International Parkinson and Movement Disorder Society.

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Animal models of α-synucleinopathy for Parkinson disease drug development

Cited by 182 publications

References 209 publications

Targeting of the class II transactivator attenuates inflammation and neurodegeneration in an alpha-synuclein model of Parkinson’s disease

Targeting of the class II transactivator attenuates inflammation and neurodegeneration in an alpha-synuclein model of Parkinson’s disease

Stereotaxic Targeting of Alpha-Synuclein Pathology in Mouse Brain Using Preformed Fibrils

New Developments in Genetic rat models of Parkinson's Disease

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