This study will test the proposition that toxic substances are involved in the cause of idiopathic Parkinson's disease (PD) by inducing, early in life, a less resilient but functional set of nigrostriatal (IMS) dopamine (DA) neurons that cannot withstand the stress placed on them later in life. Two stages of afflictions are therefore involved. The 1st is a predisposing, susceptible, vulnerable or sensitizing stage, occurring early in life, causing mostly epigenetic changes that impair the phenotype and/or reduce the number of the NS DA neurons. The 2nd, precipitating/inducing stage occurs when age-related wear-and-tear or other interventions damage the already susceptible NS DA neurons and precipitate the symptoms of PD. This hypothesis may explain the age-relatedness and sporadic nature o. PD. It may also explain juvenile (early onset) and adult onset PD, for the simple reason that for juvenile PD the 1st/susceptible stage will be more severe and is closer to threshold. Accordingly, the 2nd/inducing stage, of a constant intensity, will precipitate PD at an earlier age. The specific aims are: (1). To induce the 1st stage by administering methanol (MeOH) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to pregnant mice during the vulnerable period of the differentiation/neurogenesis of the NS DA neurons of the fetuses (about gestation days 8-12). The intent is to cause subtle or subthreshold changes to the NS DA neurons of the offsprings without impairing motor functions. (2).To induce the 2nd or precipitating stage in the mature MeOH-or MPTP-treated offsprings by increasing biological methylation via S-adenosyl-L-methionine (SAM) or challenging with MPTP. These will cause further or threshold level harm to the NS DA neurons. MPTP is a precursor for the toxin, 1-methyl-4-phenylpyridinium that targeted the NS DA neurons and is fetotoxic. MeOH is an embryo-toxin (Rogers and Mole, 1997), causes basal ganglia toxicity (Guggenhein et al, 1971; Dewitt and Martin 1988; Ley and Gali 1983; Mozaz et al, 1991; Aziz et al, 2002), covalently reacts with DNA (Chung et al, 2004) and reduces total DNA (Abbot et al, 1994). It freely crosses tissue barriers and it is a precursor for formaldehyde and formic acid. The functions, anatomy and biochemistry of the basal ganglia will be studied to assess the phenotypic changes associated with the sensitization stage induced in utero as well as to verify the precipitated PD-like changes. A new model for PD may be identified and the results may lead to the development of interventions to prevent or delay similar toxicities. The approaches will find utility in the study of other degenerative disorders by focusing on other neuronal groups.

R21NS049623

2006-03-03

2010-02-28