Animal Models of Parkinson’s Disease Induced by Toxins and Genetic Manipulation

Abstract

Parkinson’s disease (PD) is one of the most common chronic neurodegenerative disorders. It is characterized by a variety of motor (bradykinesia, rigidity, tremor, and postural instability) and nonmotor (autonomic disturbances and psychosis) symptoms. Although it can be diagnosed accurately, no therapeutic strategies can cure or completely block the progression of PD. Pathologically, PD is characterized by the severe loss of dopaminergic (DAergic) neurons in the pars-compacta nigra and the presence of proteinaceous synuclein inclusions, called Lewy bodies (LBs), which are present in neurons of the central nervous system (specific cortical regions, brain stem, and spinal cord), peripheral autonomic nervous system, enteric nervous system (ENS), and cutaneous nerves (Braak et al., 2006; Ikemura et al., 2008; Lebouvier et al., 2009). Similar to other neurodegenerative diseases, such as Alzheimer’s disease, age is the major risk factor for PD although 10% of the people with the disease are younger than 45. Although PD is regarded as a sporadic disorder, remarkably few environmental causes or triggers have been identified (Dick et al., 2007; Tanner, 2003; Taylor et al., 2005). Pesticides and herbicides are the most likely candidates for environmental agents associated with the pathogenesis of PD. On the other hand, PD characteristics are seen in a number of familial motor disorders caused by different genetic factors. Animal models of neurodegenerative diseases, including PD, have in general been quite instructive in understanding their pathogenesis. Ideally, animal models of PD, whether induced by environmental risk factors (neurotoxins) or genetic manipulations, should faithfully reproduce the clinical manifestations (behavioral abnormalities), pathological features, and molecular dysfunctions characterizing the disease. Unfortunately, animal models rarely mimic the etiology, progression, and pathology of PD completely, and in most cases, only partial insight can be gained from these studies. Despite these difficulties, animal models are considered to be very helpful in the development of therapies to treat PD. In this paper, we discuss recently developed neurotoxin-induced and genetic model animals of PD. Over the years, many chemical compounds and toxin have been identified causative agents of PD. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a representative strong neurotoxin that has been recognized from several young drug addicts developed severe parkinsonism. The addicts illegally achieved street preparations of drugs and products were contaminated with MPTP. In addition, epidemiologically, environmental neurotoxins such