Animal Models of Parkinson's Disease: Vertebrate Genetics

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.

Activation of tyrosine kinase c-Abl contributes to α-synuclein–induced neurodegeneration

“…Mutations (A53T, A30P, and E46K) or duplication or triplication of WT α-synuclein have been associated with rare forms of familial PD (9)(10)(11)(12). Many α-synuclein transgenic mouse models of the familial forms of PD due to mutations in α-synuclein have been created (7,(13)(14)(15)(16)(17). These models replicate many of the features of α-synucleinopathy-induced neurodegeneration that is present in human PD and diffuse Lewy body disease (7,(13)(14)(15)(16)(17).…”

“…Many α-synuclein transgenic mouse models of the familial forms of PD due to mutations in α-synuclein have been created (7,(13)(14)(15)(16)(17). These models replicate many of the features of α-synucleinopathy-induced neurodegeneration that is present in human PD and diffuse Lewy body disease (7,(13)(14)(15)(16)(17). Posttranslational modifications of α-synuclein such as nitrosylation, oxidation, and phosphorylation play a role in modulating α-synuclein aggregation and toxicity (18)(19)(20)(21).…”

When rejuvenation is a problem: challenges of modeling late-onset neurodegenerative disease

“…Animal models can be very useful, as they allow the disease to be explored over time at the organismal level and may enable behavioral studies to monitor disease symptoms. Some genetic mouse models of PD show α-synuclein aggregation, mitochondrial dysfunction or mild deficits in dopamine transmission or behavioral impairments (Lee et al, 2012b;Le et al, 2014). However, there is no animal model that fully captures the molecular mechanisms, pathophysiology, progressive nature and clinical symptoms of the human disease.…”

Parkinson’s Disease: New Insights

“…A promising approach to the study of PD has been so far represented by the use of animal models, including mice, for which expression profiles and data from proteomics and metabolomics are available [24], zebrafish, which shows orthologs of many PD-associated genes and can respond to toxins with a PD phenotype [25,26] and Drosophila that reproduces PD in a very accurate manner [26].…”