Differences in the soluble and insoluble proteome between primary tauopathies

IF 13 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-06-22 DOI:10.1002/alz.70401

Tomas Kavanagh, Kaleah Balcomb, Stephanie Trgovcevic, Laura Nementzik, Evgeny Kanshin, Glenda Halliday, Beatrix Ueberheide, Eleanor Drummond

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引用次数: 0

Abstract

INTRODUCTION

Primary tauopathies, including corticobasal degeneration (CBD), Pick's disease (PiD), and progressive supranuclear palsy (PSP), have aggregated tau pathology in the brain. Many other proteins are likely altered in disease; however, these have not been well characterized.

METHODS

We performed sarkosyl fractionation of post mortem human brain tissue to enrich soluble and insoluble proteins from CBD, PiD, and PSP cases (n = 5/group). We assessed differences in the soluble fraction, insoluble fraction, and protein solubility changes between diseases, followed by enrichment and correlation analysis.

RESULTS

CBD and PiD showed the greatest proteomic similarity in both the soluble and insoluble fractions, while PSP was the most divergent in comparison to other diseases. We observed critical changes in the solubility of lysosomal regulators, postsynaptic proteins, the extracellular matrix (ECM), and mitochondrial proteins.

DISCUSSION

We have contrasted the solubility patterns of proteins across three tauopathies for the first time. Protein solubility differences reveal divergence in disease processes.

Highlights

Tau isoforms are differentially soluble in primary tauopathies
PSP proteomics profile was the most divergent of the tauopathies examined
SORT1 is highly insoluble in CBD and aggregates to different extents in tauopathies
There are shifts in solubility for key signalling pathways; ROCK1 and JAK2
Unique lysosomal proteins are more insoluble in distinct tauopathies

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原发性牛头病变中可溶性和不可溶性蛋白质组的差异

原发性tau病变，包括皮质基底变性（CBD），匹克病（PiD）和进行性核上性麻痹（PSP），在大脑中聚集了tau病理。许多其他蛋白质可能在疾病中发生改变；然而，这些还没有很好地表征。方法我们对CBD、PiD和PSP病例（n = 5/组）的死后脑组织进行萨科齐分离，以富集可溶性和不溶性蛋白。我们评估了不同疾病之间可溶性部分、不可溶性部分和蛋白质溶解度变化的差异，然后进行富集和相关分析。结果CBD和PiD在可溶性和不溶性部分均表现出最大的蛋白质组相似性，而PSP与其他疾病相比差异最大。我们观察到溶酶体调节因子、突触后蛋白、细胞外基质（ECM）和线粒体蛋白的溶解度发生了重大变化。我们首次对比了蛋白质在三种牛头病中的溶解度模式。蛋白质溶解度的差异揭示了疾病过程的差异。在所检测的Tau亚型中，PSP蛋白组学谱差异最大。SORT1在CBD中高度不溶，在Tau病变中聚集程度不同，关键信号的溶解性发生了变化通路;ROCK1和JAK2独特的溶酶体蛋白在不同的牛头病变中更不溶

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.