Abstract

Progressive supranuclear palsy (PSP) is an atypical parkinsonism with prominent 4R-tau neuropathology, and the classical clinical phenotype is characterized by vertical supranuclear gaze palsy, unprovoked falls, akinetic-rigid syndrome and cognitive decline. Though PSP is generally regarded as sporadic, there is increasing evidence suggesting that a series of common and rare genetic variants impact on sporadic and familial forms of PSP. To date, more than 10 genes have been reported to show a potential association with PSP. Among these genes, the microtubule-associated protein tau (MAPT) is the risk locus with the strongest effect size on sporadic PSP in the case-control genome-wide association studies (GWAS). Additionally, MAPT mutations are the most common cause of familial PSP while the leucine-rich repeat kinase 2 (LRRK2) is a rare monogenic cause of PSP, and several other gene mutations may mimic the PSP phenotype, like the dynactin subunit 1 (DCTN1). In total, 15 MAPT mutations have been identified in cases with PSP, and the mean age at onset is much earlier than in cases carrying LRRK2 or DCTN1 mutations. GWAS have further identified several risk loci of PSP, proposing molecular pathways related to PSP. The present review focused on genetic studies on PSP and summarized genetic factors of PSP, which may help to elucidate the underlying pathogenesis and provide new perspectives for therapeutic strategies.

中文翻译：

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进行性核上性麻痹的遗传学：综述

摘要

进行性核上性麻痹（PSP）是一种以 4R-tau 神经病理学表现突出的非典型帕金森病，其经典临床表型以垂直核上性凝视麻痹、无端跌倒、运动不能-强直综合征和认知能力下降为特征。尽管 PSP 通常被认为是散发性的，但越来越多的证据表明一系列常见和罕见的遗传变异对散发性和家族性 PSP 产生影响。迄今为止，已报道超过 10 个基因与 PSP 存在潜在关联。在这些基因中，微管相关蛋白 tau ( MAPT ) 是病例对照全基因组关联研究 (GWAS) 中对散发性 PSP 影响最强的风险位点。此外，MAPT突变是家族性 PSP 的最常见原因，而富含亮氨酸的重复激酶 2 ( LRRK2 ) 是 PSP 的罕见单基因原因，其他几种基因突变可能模仿 PSP 表型，如 dynactin 亚基 1 ( DCTN1 ) 。总共在 PSP 病例中发现了 15 个MAPT突变，并且平均发病年龄比携带LRRK2或DCTN1突变的病例要早得多。GWAS进一步鉴定了PSP的几个危险位点，提出了与PSP相关的分子通路。本文重点对PSP的遗传学研究进行综述，总结PSP的遗传因素，这可能有助于阐明潜在的发病机制，并为治疗策略提供新的视角。