Association of ALS to gene-environment mediated changes in HDL proteins

描述(申请人提供)：肌萎缩侧索硬化症(ALS)或Lou Gehrig病是一种致命的神经退行性疾病，主要影响中老年人。有家族性(FALS)和散发性(SALS)两种形式的疾病，分别占病例的10%和90%。FAL的遗传原因与几个基因的突变有关，如超氧化物歧化酶、TDP-43、FUS、视神经磷酸酶、泛素蛋白2和C9ORF72。然而，SALS的病因仍然难以捉摸。几年前，我们的实验室发现，与SALS相关的对氧磷酶基因存在多态性。这些酶对某些杀虫剂和有毒物质解毒，从而成为第一个与肌萎缩侧索硬化症相关的环境相关基因。对血浆中对氧磷酶和载脂蛋白L1的进一步研究表明，SALS患者的血浆对氧磷酶和载脂蛋白L1水平显著升高。这些蛋白质存在于特定的高密度脂蛋白(HDL)颗粒上，这些颗粒具有多种功能，包括脂质和胆固醇的运输，以及保护脂蛋白免受有害氧化。在脑脊液(CSF)中也发现了类似的颗粒。因此，在这项建议中，我们使用高通量技术进一步表征了SALS患者血浆和脑脊液中选定的高密度脂蛋白种类的蛋白质组成。我们现在可以第一次确定某些高密度脂蛋白在神经退行性疾病中是如何变化的，以及它们是否与疾病过程有关。我们还将确定高密度脂蛋白相关蛋白的基因是否包含与SALS风险相关的变异，以及这些变化是否与高密度脂蛋白水平的变化有关。这些变化的有害影响的机制将在细胞培养和基因工程小鼠中进行研究。这项工作的结果将为拯救潜在的功能失调的高密度脂蛋白开辟了治疗途径，不仅在ALS等神经退行性疾病中发现，而且在更常见的心血管和代谢性疾病中也发现。

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) or Lou Gehrig disease is a fatal neurodegenerative disease that primarily affects mid-life and older adults. There are two forms of disease, familial (FALS) and sporadic (SALS), respectively comprising 10% and 90% of cases, respectively. The genetic causes of FALS have been linked to mutations in several genes such as superoxide dismutase, TDP-43, FUS, optineurin, ubiquilin 2 and C9ORF72. The etiology of SALS, however, remains elusive. A few years ago our laboratory found that there were polymorphisms in genes for enzymes called paraoxonases that were associated with SALS. These enzymes detoxify certain pesticides and toxic agents, and thus became the first environmentally related genes linked to ALS. Further studies of the paraoxonases and apolipoprotein L1 in the plasma indicate that their levels are significantly elevated in SALS patients. These proteins are found on specific high density lipoprotein (HDL) particles that have several functions including lipid and cholesterol transport and protecting lipoproteins from deleterious oxidation. Similar particles are also found in the cerebrospinal flui (CSF). Thus, in this proposal we further characterize the protein composition of selected HDL species in the plasma and CSF of SALS patients using high throughput technologies. We can now, for the first, time determine how certain HDL proteins change in a neurodegenerative disease and if they are linked to the disease process. We will also determine whether the genes for HDL-associated proteins contain variants that are associated with risk of SALS and whether these changes are related to alterations in HDL protein levels. Mechanisms of the deleterious effects of these changes will be studied in cell culture and genetically engineered mice. Results from this work will open paths to therapies to rescue potential dysfunctional HDL found not only in neurodegenerative disease such as ALS but also in more common cardiovascular and metabolic diseases.