Animal Models of Parkinson´s Disease

by: Burkhard Niewoehner
 

Introduction

Parkinson’s disease (PD) was the first neurological disease to be modelled in animals. Early models of PD used toxins which selectively targeted dopaminergic neurons, such as reserpine, 6-hydroxydopamine, and 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine. These initial models have greatly contributed to the current understanding of the pathogenesis of PD and have proven to be valuable tools in the development of novel therapeutic approaches, but have failed to mimic important characteristics of PD. Recently, it has been found that chronic systemic exposure to the pesticide rotenone can reproduce specific features of PD in rodents. Moreover, the association of a-synuclein mutations with some cases of familial PD have motivated the development of genetic models of PD in mice and Drosophila. The present essay gives a brief survey of the clinics and pathophysiology of PD, discusses the different animal models of PD currently available, and briefly compares the suitability the rodents and primates as models for human PD.

Parkinson’s disease

Parkinson’s disease (PD), first described by James Parkinson in 1817, is the second most common neurodegenerative disease, affecting about 120.000 people in the UK, with approximately 10.000 newly diagnosed cases each year, the vast majority of them in elderly people. PD is a chronically progressive disorder which develops gradually until the clinical symptomatology becomes manifest. The cardinal symptoms in fully developed parkinsonism comprise rest tremor, rigor, and bradykinesia. Further clinical manifestations are gait abnormalities and postural instability. Moreover, cognitive and psychological impairments such as dementia and depressive symptomatology have been reported in about 30% (Aarsland et al. 1996) and 40% (Cummings 1992) of PD patients respectively. The primary causal mechanism underlying these deficits is a progressive degeneration of the nigrostriatal dopaminergic (DA) pathway (see Fig.1) However, the full clinical expression of parkinsonism does not occur until the striatal DA level is reduced by about 80% (Hornykiewicz 1993) (see Fig.2). Dopamine depletion below this level is counterbalanced by compensatory mechanisms, such as increased activity of the remaining DA neurons, or an elevated expression of postsynaptic DA receptors (Deumens et al. 2002).

Fig. 1. [figure only in downloadfile]

Another pathological feature of PD is the occurrence of intracellular, eosinophilic inclusions, so called Lewy-bodies, a major component of which is a protein called a-synuclein. Although PD is usually considered a disorder specific to nigral DA neurons, it has been demonstrated that neuronal degeneration in PD patients also occurs in other DA systems, such as the ventral tegmental area (Agid et al. 1990), as well as in non-dopaminergic cell populations, including noradrenergic neurons of the locus coeruleus and dorsal vagal nucleus, serotonergic neurons of the dorsal raphe, and the cholinergic pathway from the nucleus basalis Meynert (see Jellinger 1990, for a review). These non-nigral lesions are considered to account for the cognitive and psychological aspects of PD.

Although the aetiology of PD remains unknown, there is evidence for the implication of oxidative stress and dysfunction of complex I of the mitochondrial respiratory chain in the pathogenesis of PD (Betarbet 2002). Both environmental and genetic factors have been suggested to underlie PD. The idea of an environmental contribution to the evolvement of PD derived from the discovery of the toxin 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP), which causes selective degeneration of nigral DA neurons in humans, associated with motor disturbances characteristic for PD. Other toxins that have been shown to induce nigral DA depletion include carbon monoxide (Choi and Cheon 1999), ß-carolines (Collins and Neafsey 2002), and rotenone (Betarbet et al. 2000). On the other hand, rare cases of familial PD have recently been linked to point-mutations of the a-synuclein gene (Mashlia et al. 2000)¹, indicating that there may as well be a genetic contribution to the pathogenesis of

PD2, though genetic mutations cannot today explain sporadic and late onset cases (Tanner et al. 1999).Taken together, these findings suggest that various exogenous and endogenous3 compounds can induce PD when a susceptible background in the form of a genetic predisposition exists.

Fig. 2 [figure only in downloadfile]

Animal models of Parkinson’s disease: General considerations

Why use animal models?

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1 However, most neurodegenerative disorders with Lewy-bodies are associated with abnormal accumulation of wild-type, not mutant, a-synuclein (Mashlia 2000).