Investigating cell type specific defects in protein quality control across the genetic landscape of Parkinson’s disease

帕金森病（PD）是第二常见的进行性神经退行性疾病。目前没有治愈方法，只有短暂的运动症状对症治疗。如果我们想在最早阶段解决PD并减缓其进展，那么迫切需要创新的治疗方法来改变神经元死亡之前的最早非运动症状。不幸的是，这是阻碍了对早期神经元缺陷的起源知识不足。在这个研究项目中，我将解决这个知识差距，以获得重要的见解的分子途径，这是影响早期的PD。超过20个基因已被链接到家族形式的PD。大多数“PD基因”参与蛋白质质量控制的各个方面，但目前仍不清楚这些不同的分子缺陷最终如何在重叠的病理学中表现出来。果蝇是研究神经退行性疾病的极好模式生物，因为70%的人类疾病基因在果蝇中是保守的，和PD病理学的关键特征被概括，包括早期症状，如睡眠障碍或嗅觉受损。有趣的是，一些PD果蝇模型在幼年动物脑中的相同细胞类型中表现出类似的转录组变化。这些失调的基因主要影响蛋白质稳态途径，并且可以通过增加最受影响的细胞类型中突触处的蛋白质周转能力来挽救神经元功能障碍。我推测，不同的致病性PD变异体通常会聚到一个共同的中枢枢纽，在疾病的早期，在突触前末梢中解除蛋白质质量控制途径的调节，这有助于神经元功能障碍，死亡。在拟议的项目中，我将通过采购包含所有已知致病性PD突变的独特果蝇标本来调查这一假设。我将评估PD突变如何影响突触末梢的细胞蛋白质稳态网络，包括全局和局部。我将通过将多功能果蝇遗传学和生化检测与最先进的单细胞RNA测序相结合来确定常见的脆弱性途径。随后，我将验证所确定的中央枢纽和机制，在诱导多能干细胞衍生的神经元从PD患者窝藏相应的mutations.Thus，我将确定共同的关键因素，在细胞类型特异性的脆弱性通路，在疾病的早期失调整个家族遗传空间的PD。通过研究家族性PD的分子机制，我也将对散发性PD的病因学有新的认识。我将获得创新的治疗目标，以改变疾病的进展。2.我将揭示蛋白质稳态如何维持突触功能和3。回答为什么这个过程在PD早期受到影响。

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder. There is currently no cure, and only transient symptomatic treatments of the motor symptoms are available. If we want to tackle PD in its earliest stages and slow its progression, there is an urgent need for innovative therapeutics that modify the earliest non-motor symptoms that precede neuronal death. Unfortunately, this is hampered by insufficient knowledge on the origins of early neuronal defects. In this research project, I will address this knowledge gap to gain important insights into the molecular pathways, which are affected early in PD.More than 20 genes have been linked to familial forms of PD. Most “PD genes” are involved in various aspects of protein quality control, but it remains unclear how these diverse molecular defects ultimately manifest in an overlapping pathology.Drosophila melanogaster is an excellent model organism for studying neurodegenerative diseases as 70% of human disease genes are conserved in flies, and key features of PD pathology are recapitulated including early symptoms such as sleep disorders or impaired sense of smell.Intriguingly, a few PD fly models exhibit similar transcriptome changes in the same cell types in the brains of young animals. These deregulated genes mainly affect protein homeostasis pathways and neuronal dysfunction can be rescued by increasing the protein turnover capacity at synapses in the most affected cell types.Therefore, I speculate that different pathogenic PD variants generally converge onto a common central hub that deregulates protein quality control pathways in the presynaptic terminal early in the disease and that this contributes to the neuronal dysfunction that precedes neuronal death.In the proposed project, I will investigate this hypothesis by sourcing a unique Drosophila collection containing all known pathogenic PD mutations. I will assess how the PD mutations affect the cellular protein homeostasis network, both globally and locally, in synaptic terminals. I will determine common vulnerability pathways by combining versatile fly genetics and biochemical assays with state-of-the-art single cell RNA sequencing. Subsequently, I will validate the identified central hubs and mechanisms in induced pluripotent stem cell derived neurons from PD patients harboring the corresponding mutations.Thus, I will identify the common key factors in the cell type specific vulnerability pathways that are deregulated early in disease across the familial genetic space of PD. By studying the molecular mechanisms underlying familial PD, I will also gain novel insights into the etiology of sporadic PD.If successful, this project will deliver three important results: 1. I will obtain innovative therapeutic targets to modify disease progression. 2. I will reveal how protein homeostasis maintains synaptic function and 3. answer why this process is affected early in PD.