Accumulation of aberrant misfolded proteins is a major hallmark of several neurodegenerative diseases. Intracellular accumulations of such abnormal proteins are selectively cleared by the ubiquitin-proteasome system (UPS). But how the failure of misfolded protein degradation cause proteinopathies is still an unanswered question?. Previous studies have suggested that few selective quality control (QC) E3 ubiquitin ligase from the UPS can selectively target insoluble aggregated proteins for their intracellular degradation. Few reports suggest that lack or aberrant functions of QC E3 ubiquitin ligases can be a possible causative factor of neurodegeneration and aging. Earlier findings indicated that leucine-rich repeat and sterile alpha motif containing-1 (LRSAM1) is associated with Charcot-Marie-Tooth Type 2P (CMT2P) disease in which loss of LRSAM1 function sensitizes peripheral axons for degeneration. Here, our current study for the first time demonstrates that E3 ubiquitin Ligase LRSAM1 is a really interesting new gene (RING) class protein which suppresses the accumulation of misfolded protein aggregates and also alleviates their deleterious cytotoxic effects. We have also observed that LRSAM1 expression is elevated under neurodegenerative stress conditions, and partial depletion of LRSAM1 endogenous levels aggravates mitochondrial abnormalities and severely affects cell survival during proteotoxic insults. Overall, our current finding indicates that LRSAM1 can alleviate cytotoxic insults mediated by a variety of neurodegeneration linked proteotoxic stress events, and most likely LRSAM1 interplay a significant role in between different components of cellular protein quality control mechanism. This study will also allow us to better comprehend the problem of proteinopathies linked with aberrant protein accumulation and open new possibilities to better elucidate the molecular mechanisms involved in the pathologies of neurodegeneration and aging.

异常错误折叠蛋白的积累是几种神经退行性疾病的主要标志。这种异常蛋白的细胞内积累被泛素-蛋白酶体系统（UPS）选择性清除。但是，错误折叠的蛋白质降解的失败如何引起蛋白质病仍然是一个尚未解决的问题？先前的研究表明，很少有来自UPS的选择性质量控制（QC）E3泛素连接酶可以选择性地靶向不溶性聚集蛋白进行细胞内降解。很少有报道表明QC E3泛素连接酶功能的缺乏或异常可能是神经变性和衰老的可能原因。较早的发现表明，富含亮氨酸的重复序列和含有1的无菌α基序（LRSAM1）与Charcot-Marie-Tooth Type 2P（CMT2P）疾病相关，其中LRSAM1功能的丧失使外周轴突变性。在这里，我们目前的研究首次证明E3泛素连接酶LRSAM1是一个非常有趣的新基因（RING）类蛋白，它抑制了错误折叠的蛋白聚集体的积累，并减轻了其有害的细胞毒性作用。我们还观察到，在神经退行性应激条件下，LRSAM1表达升高，并且内源水平的LRSAM1的部分耗竭加剧了线粒体异常，并严重影响了蛋白毒性损伤期间的细胞存活。总体，我们目前的发现表明，LRSAM1可以减轻多种神经退行性蛋白毒性应激事件介导的细胞毒性损伤，并且很可能LRSAM1在细胞蛋白质质量控​​制机制的不同组成部分之间起着重要作用。这项研究还将使我们能够更好地理解与异常蛋白质积累有关的蛋白质病问题，并开辟新的可能性以更好地阐明与神经退行性变和衰老的病理过程有关的分子机制。