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Review
. 2012 Oct 1;2(10):a009324.
doi: 10.1101/cshperspect.a009324.

Animal models of Parkinson's disease: vertebrate genetics

Yunjong Lee  1 , Valina L Dawson, Ted M Dawson
Affiliations
Review

Animal models of Parkinson's disease: vertebrate genetics

Yunjong Lee et al. Cold Spring Harb Perspect Med. .

Abstract

Parkinson's disease (PD) is a complex genetic disorder that is associated with environmental risk factors and aging. Vertebrate genetic models, especially mice, have aided the study of autosomal-dominant and autosomal-recessive PD. Mice are capable of showing a broad range of phenotypes and, coupled with their conserved genetic and anatomical structures, provide unparalleled molecular and pathological tools to model human disease. These models used in combination with aging and PD-associated toxins have expanded our understanding of PD pathogenesis. Attempts to refine PD animal models using conditional approaches have yielded in vivo nigrostriatal degeneration that is instructive in ordering pathogenic signaling and in developing therapeutic strategies to cure or halt the disease. Here, we provide an overview of the generation and characterization of transgenic and knockout mice used to study PD followed by a review of the molecular insights that have been gleaned from current PD mouse models. Finally, potential approaches to refine and improve current models are discussed.

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Figures

Figure 1.
Figure 1.
Options for conditional PD animal models. Schematics showing tetracycline-regulated conditional transgenic approaches that can offer reversible induction of dominant PD-causing alleles in desired tissues at specific time points. (A) The transgene can be expressed in tissues in which a tissue-specific promoter (pTissue specific) drives tTA. The tetracycline analog doxycycline (DOX) binds to tTA and suppress its ability to activate the Tet-responsive promoter (pTet), thus enabling temporal and reversible regulation over transgene expression. (B) To circumvent the shortage of strong driver lines, the constitutively active chicken β-actin promoter (pCAG) can be used to express tTA, which, in turn, binds and activates pTet downstream. tTA transcription is suppressed by a stuffer sequence downstream from pCAG, but Cre-mediated removal of the stuffer will unleash DOX-regulated reversible transgenic overexpression in specific regions. (C) In the case of autosomal-recessive PD models, a mouse line, which expresses tamoxifen-activated Cre-ER under the control of tissue-specific promoter, can be crossed with conditional lines that have loxP-flanked genes of interest. Temporal regulation over gene deletion will offer the opportunity to avoid potential compensatory pathways that are thought to mask or diminish expected pathological phenotypes in conventional KO mouse models of PD.
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