Gene Dose Effect of DJ-1 and PINK1 on Tissue Degeneration

描述（由申请人提供）：我们已经产生了携带DJ-1和PINK 1无效等位基因的突变小鼠。这两个基因都与早发性家族性帕金森病（PD）的隐性形式有关。我们已发表和未发表的数据表明，DJ-1缺陷小鼠发展渐进的年龄依赖性运动功能减退，多巴胺系统失调，体重减轻和骨骼肌变性。类似地，最近在PINK 1缺陷的果蝇中报道了肌肉变性。相比之下，PINK 1基因敲除小鼠仅表现出非常轻微的表型（我们未发表的数据）。最近，已经报告了DJ-1和PINK 1突变杂合子的PD病例。我们推断DJ-1和PINK 1可能是生物化学途径的组成部分，DJ-1; PINK 1双突变小鼠可能会产生重要的表型，这些表型不是由DJ-1缺陷或PINK 1缺陷单独捕获的。成功获得DJ-1、PINK 1双无效等位基因（DJ-1和PINK 1相距11.9Mb）。令人惊讶的是，DJ-1和PINK 1的缺乏导致早期胚胎死亡，进一步强化了DJ- 1和PINK 1可能是生物化学途径的组成部分的想法，这对多种组织中的细胞存活至关重要。我们建议产生一系列的突变小鼠品系与中间DJ-1 PINK 1基因剂量，以获得早期胚胎致死（DJ-1，PINK 1双突变体）和肌肉变性之间的中间表型，但没有多巴胺神经元损失（DJ-1单突变体）。这些小鼠将是研究DJ-1和PINK 1功能及其相互作用与帕金森病以及其他退行性疾病发病机制相关的重要工具。公共卫生相关性：最近发表的研究和我们自己的数据表明，两个基因，DJ-1和PINK 1，可能一起工作，并在帕金森病和其他退行性疾病中发挥重要作用。我们建议生成动物模型，以详细研究这种对不同退行性疾病很重要的生化途径。我们的研究结果将指出新的治疗靶点和治疗方法。

DESCRIPTION (provided by applicant): We have generated mutant mice that harbor null alleles of DJ-1 and PINK1. Both genes are linked to recessive form of early-onset familial Parkinson's disease (PD). Our published and unpublished data indicate that DJ-1 deficient mice develop progressive age-dependent hypolocomotion, dopamine system dysregulation, body weight loss and skeletal muscle degeneration. Similarly, muscle degeneration has recently been reported in PINK1 deficient flies. In contrast, PINK1 null mice only display very mild phenotypes (our unpublished data). Recently, PD cases that are heterozygous for DJ-1 and PINK1 mutations have been reported. We reason that DJ-1 and PINK1 might be components of a biochemical pathway and that DJ-1;PINK1 double mutant mice might develop important phenotypes that are not captured by either DJ-1 deficiency or PINK1 deficiency alone. We have successfully obtained DJ-1;PINK1 double null allele (DJ-1 and PINK1 are 11.9 Mb apart). To our surprise, deficiency for both DJ-1 and PINK1 leads to early embryonic lethality, further reinforcing the idea that DJ- 1 and PINK1 might be components of a biochemical pathway that is crucial for cell survival in multiple tissues. We propose to generate a series of mutant mouse lines with intermediate DJ-1 PINK1 gene doses in order to obtain intermediate phenotypes between early embryonic lethality (DJ-1;PINK1 double mutants) and muscle degeneration but no dopamine neuron loss (DJ-1 single mutants). These mice will be important tools to investigate DJ-1 and PINK1 function and their interactions related to the pathogenesis in Parkinson)s disease as well as in other degenerative diseases. PUBLIC HEALTH RELEVANCE: Recently published studies and our own data suggest that two genes, DJ-1 and PINK1, may work together and play important roles in Parkinson's disease and other degenerative diseases. We propose to generate animal models to examine in detail such a biochemical pathway that is important for different degenerative disease. Our results will point to new therapeutic targets and therapeutic approaches.