Overcoming proteasome impairment with small molecules

除了最近批准的抗体Aducanumab外，Aducanumab可能有助于早发患者， 没有治疗方法来预防、减缓或治愈这样的神经退行性疾病 阿尔茨海默病和相关痴呆(ADRD)。目前的治疗只是暂时的 抑制疾病症状。这项工作旨在研究小分子20S蛋白酶体。 激活是一种新的、创新的治疗策略，以减缓和/或防止疾病进展。 淀粉样β蛋白、α-突触核蛋白和二肽重复单位等蛋白质本质上是无序的。 蛋白质(IDPs)，有很高的寡聚和聚集积累的趋势。 这些低聚物导致神经毒性的确切机制是复杂的，而且仍然是 辩论过了。然而，人们普遍认为，这些易于聚集的蛋白质的积累 结果是(1)有毒寡聚物种和(2)蛋白酶体损伤，这是两个典型的 神经退行性疾病的特征，最终导致疾病进展。 在这项探索性的R21拨款中，我们开创了药物发现的新范式，这是 重点是通过加强20年代的活动来防止国内流离失所者的积累 使用小分子的蛋白酶体。我们的假设是小分子20S蛋白酶体 增强会导致IDPs的降解，从而防止和恢复蛋白酶体 功能，被这些IdP寡聚体削弱。为了检验这一假设，我们将探索 两种新的但截然不同的20S蛋白酶体增强剂的有效性 由我们的研究小组发表，因为他们有能力(1)防止IdP积累和(2)恢复 蛋白酶体功能受损。 影响：根据美国国家老龄研究所的数据，阿尔茨海默病是全球第六大死因 在美国，然而，它仍然大多没有有效的治疗选择。圆满完成这项工作 将验证一种新的策略，该策略解决了这些疾病发病的两个基本步骤 这可能为治疗这些毁灭性的痴呆症提供一种治疗策略。

Other than the recently approved antibody, Aducanumab, which may help early onset patients, there are no therapeutic treatments to prevent, slow or cure neurodegenerative diseases such Alzheimer's disease and related dementias (ADRD). Current treatments only temporarily suppress disease symptoms. This work aims to investigate small molecule 20S proteasome activation as a new, innovative therapeutic strategy to slow and/or prevent disease progression. Proteins such as amyloid-Beta, alpha-synuclein and dipeptide repeat units are intrinsically disordered proteins (IDPs), which have a high tendency to oligomerize and aggregate upon accumulation. The exact mechanism by which these oligomers induce neurotoxicity is complex and still debated. However, it is widely accepted that accumulation of these aggregation-prone proteins results in (1) toxic oligomeric species and (2) proteasome impairment, which are two classic hallmarks of neurodegenerative disorders that ultimately drive disease progression. In this exploratory R21 grant, we are pioneering a new paradigm in drug discovery, which is focused on preventing the accumulation of IDPs by enhancing the activity of the 20S proteasome using small molecules. Our hypothesis is that small molecule 20S proteasome enhancement will induce the degradation of IDPs, and thereby prevent and restore proteasome function, that was impaired by these IDP oligomers. To test this hypothesis, we will explore the efficacy of two new, but distinct classes of 20S proteasome enhancers, discovered and published by our research group, for their ability to (1) prevent IDP accumulation and (2) restore impaired proteasome function. Impact: According to the National Institutes of Aging, AD is the 6th leading cause of death in the US, yet it remains mostly without effective treatment options. Successful completion of this work will validate a new strategy that tackles two fundamental steps in the pathogenesis of these disorders, which may provide a therapeutic strategy to treat these devastating dementias.