FETAL AND ENVIRONMENTAL BASIS OF PARKINSON'S DISEASE

描述（由申请人提供）：本研究将测试以下命题：毒性物质通过在生命早期诱导黑质纹状体（IMS）多巴胺（DA）神经元的弹性较低但功能性较强的一组神经元参与特发性帕金森病（PD）的病因，这些神经元无法承受生命后期对其施加的压力。因此，涉及两个阶段的痛苦。第一个阶段是一个易患的，易感的，脆弱的或致敏的阶段，发生在生命早期，主要引起表观遗传变化，损害表型和/或减少的NS DA神经元的数量。第二个阶段，沉淀/诱导阶段发生在与年龄相关的磨损或其他干预损害已经易感的NS DA神经元并沉淀PD症状时。这一假说可能解释了年龄相关性和散发性的性质。警局它也可以解释青少年（早发）和成人发病PD，原因很简单，对于青少年PD，第一/易感阶段将更严重，更接近阈值。因此，恒定强度的第二/诱导阶段将在更早的年龄沉淀PD。具体目标是：（1）.在胎儿NS DA神经元分化/神经发生的脆弱期（约妊娠8-12天），通过给予妊娠小鼠甲醇（MeOH）或1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）诱导第1阶段。其目的是在不损害运动功能的情况下对后代的NS DA神经元造成微妙或阈下的变化。（2）通过S-腺苷-L-甲硫氨酸（SAM）增加甲基化或MPTP攻击，诱导成熟的MeOH或MPTP处理的后代出现第2期或沉淀期。这些将对NS DA神经元造成进一步或阈值水平的损害。MPTP是毒素1-甲基-4-苯基吡啶鎓的前体，其靶向NS DA神经元并且具有胎儿毒性。MeOH是一种胚胎毒素（Rogers和Mole，1997），可引起基底神经节毒性（Guggenhein等人，1971; Dewitt和Martin 1988; Ley和Gali 1983; Mozaz等人，1991; Aziz等人，2002），与DNA发生共价反应（Chung等人，2004）并减少总DNA（Abbot等人，1994）。它可以自由穿过组织屏障，是甲醛和甲酸的前体。将研究基底神经节的功能、解剖学和生物化学，以评估与子宫内诱导的致敏阶段相关的表型变化，并验证沉淀的PD样变化。可能会发现一种新的PD模型，其结果可能会导致干预措施的发展，以预防或延迟类似的毒性。这些方法将通过关注其他神经元组在其他退行性疾病的研究中找到实用性。

DESCRIPTION (provided by applicant): 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.