Genetically engineered mouse models of Parkinson's disease

Abstract

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, affecting more than 1% of the population over age 60. The most common feature of PD is a resting tremor, though there are many systemic neurological effects, such as incontinence and sleep disorders. PD is histopathologically identified by the presence of Lewy bodies (LB), proteinaceous inclusions constituted primarily by α-synuclein. To date, there is no effective treatment to slow or stop disease progression. To help understand disease pathogenesis and identify potential therapeutic targets, many genetic mouse models have been developed. By far the most common of these models are the wildtype and mutant α-synuclein transgenic mice, because α-synuclein was the first protein shown to have a direct effect on PD pathogenesis and progression. There are many other gene-disrupted or -mutated models currently available, which are based on genetic anomalies identified in the human disease. In addition, there are also models which examine genes that may contribute to disease onset or progression but currently have no identified causative PD mutations. These genes are part of signaling pathways important for maintaining neuronal function in the nigrostriatal pathway. This review will summarize the most commonly used of the genetic mouse models currently available for PD research. We will examine how these models have expanded our understanding of PD pathogenesis and progression, as well as aided in identification of potential therapeutic targets in this disorder.

Figure 1. Findings characteristic of the spectrum of pathology found in patients with Parkinson’s disease

A. In this hematoxylin and eosin stained section of the substantia nigra, a Lewy body (arrow) is evident in a neuromelanin containing neuron. B. Ubiquitin immunostaining of the cingulate gyrus highlights a cortical Lewy body (brown staining indicated by the arrow).

Figure 2. Schematic of PD mouse model-associated pathology

Categories of genetic mouse models of PD which were discussed (α-synuclein dysfunction, proteasome dysfunction, mitochondrial dysfunction, nigrostriatal pathway dysfunction, LRRK2 dysfunction and synphilin-1 dysfunction) show PD-related pathologies associated with each category that result in the generation of PD mouse models.

Figure 3. Lessons from genetic mouse models of PD

Mouse models of PD have shed light on some of the key proteins and cell signaling pathways which seem to contribute to disease pathogenesis, as well as helped us identify candidate therapeutic targets/compounds which may help to alleviate PD symptoms and possibly slow or halt the progression of neuropathology.