Novel Targets that Modulate Multiple Adult Models of ALS in Drosophila

肌萎缩侧索硬化症（ALS），俗称卢伽雷氏病，是一种灾难性的疾病， 选择性地累及脑和脊髓中的运动神经元的神经变性疾病，导致进行性肌肉无力和萎缩。据估计，它影响2/10000人，在3-5年内总是致命的，并且完全缺乏治疗方法。导致该疾病的潜在生物学和分子机制尚未完全了解。超过90%的病例是未知的遗传起源（散发性ALS）。全基因组关联研究已经确定了20多个与家族性ALS相关的不同基因（占总病例的10%），表明复杂的潜在遗传结构。由于缺乏治疗性干预措施，开发新疗法的需求很大。其中一个关键是更好地了解ALS表型背后的分子和遗传原因。通过在果蝇中进行平行遗传疾病模型筛选，我们发现磷酸脂酶D（PLD）的突变及其上游细胞内途径中的至少六种组分，有助于抑制和控制TDP-43和FUS突变对神经系统的毒性影响，表明PLD途径是重要的潜在ALS靶点。这种信号通路是多功能的，与癌症以及其他神经退行性疾病有关。我们还确定了VEGF/PDGF生长因子途径（Pvf-Pvr在果蝇），一个可能的上游信号输入到PLD，作为一个有效的调制器ALS表型。深入分析以了解PLD和VEGF/PDGF对ALS表型影响的具体机制，在将其作为未来的治疗靶点之前至关重要。在这里，我们建议进一步利用果蝇的优势，以确认PLD通路调制的变化可以防止进行性的，成年发作的神经肌肉衰竭。根据我们将获得的结果，这个探索性项目（R21）可能会成为证明基于R 01机制的未来分析的基础。

Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig’s disease, is a catastrophic neurodegenerative disorder that selectively involves motor neurons in the brain and spinal cord, resulting in progressive muscle weakness and atrophy. It is estimated to affect 2/10000 people, is invariably lethal within 3-5 years, and completely lacks therapeutic treatments. The underlying biology and molecular mechanisms leading to the disease are not well understood. More than 90% of the cases are of unknown genetic origin (sporadic ALS). Genome-wide association studies have identified more than twenty different genes associated with familial ALS (10% of total cases), indicating a complex underlying genetic architecture. Given the paucity of therapeutic interventions there is a great unmet need to develop novel therapies. A key to this is a better molecular and genetic understanding of the causes underlying ALS phenotypes. Through parallel genetic disease model screens in Drosophila, we found that mutations in phospho-lipase D (PLD), and at least six components in its upstream intracellular pathway, serve to suppress and control the toxic impact of TDP-43 and FUS mutations in the nervous system, indicating that the PLD pathway is a significant potential ALS target. This signaling pathway is multifunctional and has been linked to cancer as well as other neurodegenerative diseases. We also identified the VEGF/PDGF growth factor pathway (Pvf-Pvr in Drosophila), a likely upstream signaling input to PLD, as an potent modulator of ALS phenotypes. Deeper analysis to understand the specific mechanisms underlying the impact of PLD and VEGF/PDGF on ALS phenotypes is essential before they can be pursued as future therapeutic targets. Here, we propose to further leverage the strengths of Drosophila to confirm that changes in the PLD pathway modulation can prevent progressive, adult-onset neuromuscular failure. Depending on the results we will obtain, this exploratory project (R21) may form the basis to justify future analysis under R01-based mechanism.