Genetic animal models of Parkinson's disease

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by the degeneration of dopamine (DA) and non-DA neurons, the almost uniform presence of Lewy bodies, and motor deficits. Although the majority of PD is sporadic, specific genetic defects in rare familial cases have provided unique insights into the pathogenesis of PD. Through the creation of animal and cellular models of mutations in LRRK2 and alpha-synuclein, which are linked to autosomal-dominant PD, and mutations in parkin, DJ-1, and PINK1, which are responsible for autosomal-recessive PD, insight into the molecular mechanisms of this disorder are leading to new ideas about the pathogenesis of PD. In this review, we discuss the animal models for these genetic causes of PD, their limitations, and value. Moreover, we discuss future directions and potential strategies for optimization of the genetic models.

Figure 1. Mechanisms of Autosomal Dominant PD

Mutations (A53T, A30P, E46K) or increased levels (triplication or duplication) of α-synuclein lead to aggregation and fibrillization. Features common to sporadic PD such as nitric oxide (NO), reactive oxygen species (ROS), and mitochondrial dysfunction also leads to α-synuclein aggregation. Agents or genetic modifications that inhibit α-synuclein aggregation are protective, whereas enhancing α-synuclein aggregation promotes neurodegeneration. Truncation of α-synuclein accelerates aggregation and participates in the degenerative process. α-Synuclein is degraded by both the ubiquitin proteasome system and the autophagic/lysosomal system. Mutant and aggregated forms of α-synuclein inhibit the UPS and the autophagic/lysosomal system as well as the mitochondria setting in motion feed forward cycles (indicated by green circular arrows) of enhanced accumulation and aggregation of α-synuclein (see text). LRRK2 mutations ( G2019S, R1441C/G/H, Y1699C and I2020T) lead to neurodegeneration that is kinase-dependent and GTP-binding dependent (not shown). LRRK2 shares some pathogenic mechanisms with PD due to α-synuclein since a consistent pathologic feature of patients with LRRK2 mutations is the presence of α-synuclein inclusions through unclear mechanisms (?). Mitochondrial dysfunction enhances LRRK2 neurodegeneration in some models through unclear mechanisms (?). Glucocerebrosidase and ATP13A2 genetically interact with α-synuclein and also share common pathogenic mechanisms (not shown).

Figure 2. Mechanisms of Autosomal Recessive PD

Loss of function mutations in PINK1, parkin and DJ-1 cause PD. PINK1 is a mitochondrial kinase in which mutations impair its kinase activity. PINK1 acts upstream of parkin to ultimately impair mitochondrial function through as yet unknown mechanisms. Parkin is inactivated by genetic mutations or nitric oxide (NO), reactive oxygen species (ROS), dopamine (DA) or in sporadic PD, which impairs parkin’s ubiquitin E3 ligase activity. This either leads to accumulation of as of yet identified pathogenic substrate or it impairs ubiquitin dependent signaling that ultimately lead to mitochondrial dysfunction and neurodegeneration. Mutations in DJ-1 lead to a loss of its chaperone activity as well as impairing its peroxidase activity among other functions, which ultimately leads to mitochondrial dysfunction and neurodegeneration.

Figure 3. Current and Future Experimental PD Mouse Models

A. Both mutant α-synuclein and mutant LRRK2 transgenic mice do not have loss of DA neurons. One possible explanation is that the transgenes are expressed early in development leading to compensatory mechanisms that prevent degeneration of DA neurons. In a similar manner, parkin, PINK1 and DJ-1 are knocked out in the germline and there may be compensatory mechanisms that also prevent degeneration of DA neurons and provide an environment that promotes DA neuronal survival (see text). B. Strategies to potentially circumvent the compensatory mechanisms that possibly account for the survival of DA neurons in both the autosomal dominant and autosomal recessive models. For the autosomal dominant models LRRK2 and α-synuclein transgenic mice under the transcriptional control of the tetracycline operator (tetO) could be bred to different tetracycline transactivator (tTA) mice to drive expression in different neuronal populations and/or glia. Expression could be turned on in adults to avoid developmental compensation. For autosomal recessive models parkin, PINK1 or DJ-1, Cre-Lox recombination could be used to avoid developmental compensation, which may mask the true pathophysiologic action of parkin, PINK1 or DJ-1. Adeno associated virus (AAV) or lentivirus could be used to deliver Cre in adulthood and to specific neuronal populations and Tamoxifen sensitive-Cre mice could drive expression in different neuronal populations and/or glia. Expression could be turned on in adults to avoid developmental compensation.