Molecular analysis of SORL1 function and dysfunction in Alzheimer's disease

项目总结/摘要 阿尔茨海默病（AD）是一种破坏性痴呆，以罕见的家族形式或常见的形式发生， 零星的形式。目前对AD致病机制的理解是不完整的， 临床试验未能显示出治疗效果，突出了更好地了解AD的必要性 致病机制，寻找新的干预策略。内体运输失调是 越来越多地被认为是AD发病机制中的病理中心，但内体蛋白的分子基础 AD的功能障碍仍不清楚。最近发现的内体运输调节因子SORL 1（sortilin- 相关受体1，也称为SORLA或LR 11）作为早发性和迟发性 发病AD开辟了一个新的途径，研究致病机制，触发内体 功能障碍和神经退行性变。SORL 1已成为常染色体- 显性家族性AD，SORL 1截短突变功能丧失，赋予高致病性， 与三种众所周知的家族性AD基因突变引起的程度相似：淀粉样前体 蛋白（APP）和早老素1和2。此外，SORL 1基因编码区的错义变体 已被确定为发展为散发性AD的遗传风险因素。SORL 1是一种分选受体 在控制内体，trans-Golgi网络（TGN）和质膜之间的货物运输。 越来越多的证据表明，SORL 1对A β积累起关键的神经保护作用， 通过促进APP从内体运输到TGN和细胞表面，促进A β表达， 运输至溶酶体进行降解，并维持内-溶酶体系统的完整性。尽管 强有力的证据表明，SORL 1功能障碍与AD发病机制有关， SORL 1的功能仍然知之甚少。拟议的项目旨在弥补这一知识差距， 开展创新研究，阐明SORL 1调节机制及其在AD中的改变。的 该项目产生的发现和新的见解将促进我们对SORL 1的理解 功能障碍和内体运输失调，并可能指出新的治疗策略， AD治疗。

Project Summary / Abstract Alzheimer's disease (AD) is a devastating dementia that occurs either in rare, familial forms or in common, sporadic forms. Current understanding of AD pathogenic mechanisms is incomplete, and amyloidocentric clinical trials have failed to show therapeutic efficacy, highlighting the need for a better understanding of AD pathogenic mechanisms to find new strategies of intervention. Dysregulated endosomal trafficking is increasingly recognized as a pathological hub in AD pathogenesis, but the molecular basis of endosomal dysfunction in AD remains unclear. Recent discovery of endosomal trafficking regulator SORL1 (sortilin- related receptor 1, also known as SORLA or LR11) as a major risk factor for both early-onset and late- onset AD opens up a new avenue for studying the pathogenic mechanisms that trigger endosomal dysfunction and neurodegeneration in AD. SORL1 has emerged as the fourth gene for autosomal- dominant familial AD, with loss-of-function SORL1 truncation mutations conferring high pathogenicity to a similar extent as that caused by mutations in the three well-known familial AD genes: amyloid precursor protein (APP) and presenilins 1 and 2. Furthermore, missense variants in the coding region of SORL1 gene have been identified as a genetic risk factor for development of sporadic AD. SORL1 is a sorting receptor in the control of cargo trafficking between endosome, trans-Golgi network (TGN), and plasma membrane. Increasing evidence indicates that SORL1 plays a key neuroprotective role against A accumulation and neurodegeneration by promoting APP trafficking from endosome to TGN and to cell surface, facilitating A trafficking to lysosome for degradation, and maintaining the integrity of the endo-lysosomal system. Despite strong evidence linking SORL1 dysfunction to AD pathogenesis, the molecular mechanisms that regulate SORL1 function remain poorly understood. The proposed project aims to address this knowledge gap and perform innovative research to elucidate SORL1 regulation mechanisms and their alterations in AD. The findings and novel insights generated from this project will advance our understanding of SORL1 dysfunction and endosomal trafficking dysregulation in AD and may point to new therapeutic strategies for AD treatment.