TMEM106B C-terminal fragments aggregate and drive neurodegenerative proteinopathy in transgenic Caenorhabditis elegans

IF 13 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2024-12-23 DOI:10.1002/alz.14468

Ruben Riordan, Aleen Saxton, Marina Han, Pamela J. McMillan, Rebecca L. Kow, Nicole F. Liachko, Brian C. Kraemer

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Abstract

INTRODUCTION

Genetic variation in the lysosomal and transmembrane protein 106B (TMEM106B) modifies risk for several neurodegenerative disorders, especially frontotemporal lobar degeneration (FTLD). The C-terminal (CT) domain of TMEM106B occurs as fibrillar protein deposits in the brains of dementia patients.

METHODS

To determine the TMEM CT aggregation propensity and neurodegenerative potential, we generated transgenic Caenorhabditis elegans expressing the human TMEM CT fragment aggregating in FTLD cases.

RESULTS

Pan-neuronal expression of human TMEM CT in C. elegans causes severe neuronal dysfunction driving neurodegeneration. Cytosolic aggregation of TMEM CT proteins accompanied by behavioral dysfunction and neurodegeneration. Loss of pgrn-1 did not modify TMEM CT phenotypes suggesting TMEM CT aggregation occurs downstream of PGRN loss of function. The mechanistic drivers of TMEM106B proteinopathy appear distinct from known modifiers of tauopathy.

DISCUSSION

Our data demonstrate that TMEM CT aggregation can kill neurons. TMEM106B transgenic C.elegans provide a useful model for characterizing TMEM106B proteinopathy-mediated neurodegeneration in FTLD.

Highlights

Pan-neuronal expression of human TMEM106B C-terminal fragments (TMEM CT) in C. elegans neurons drives a suite of disease-related phenotypes useful for modeling the molecular and cellular features of TMEM106B neuropathology.
TMEM CT expression results in extensive TMEM aggregation and accumulation of highly detergent insoluble protein species.
TMEM CT expression causes moderate to severe neuronal dysfunction dependent on TMEM CT abundance as measured by stereotypical behavioral readouts.
TMEM CT expression drives significant neurodegenerative changes.
Dendra2 tagged TMEM exhibits similar properties to untagged TMEM allowing ready visualization of the protein.
TMEM CT aggregates accumulate adjacent to but not within lysosomes.
PGRN loss of function does not impact TMEM CT toxicity.
Modifiers of tau and TDP-43 proteinopathies have little impact on TMEM CT-related neurodegenerative phenotypes.

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TMEM106B C端片段聚集并驱动转基因秀丽隐杆线虫的神经退行性蛋白病变

溶酶体和跨膜蛋白106B （TMEM106B）的遗传变异改变了几种神经退行性疾病的风险，特别是额颞叶变性（FTLD）。TMEM106B的C端（CT）结构域在痴呆患者的大脑中以纤维蛋白沉积的形式发生。方法利用转基因秀丽隐杆线虫（Caenorhabditis elegans）表达在FTLD病例中聚集的人TMEM CT片段，测定其TMEM CT聚集倾向和神经退行性潜能。结果人TMEM CT在秀丽隐杆线虫中表达span‐神经元导致严重的神经元功能障碍，驱动神经退行性变。伴有行为障碍和神经退行性变的TMEM CT蛋白胞浆聚集。pgrn‐1的缺失并未改变TMEM CT表型，这表明TMEM CT聚集发生在pgrn功能缺失的下游。TMEM106B蛋白病变的机制驱动因素似乎不同于已知的牛头病变的修饰因子。我们的数据表明TMEM CT聚集可以杀死神经元。TMEM106B转基因秀丽隐杆线虫为表征TMEM106B蛋白病介导的FTLD神经变性提供了一个有用的模型。人类TMEM106B C端片段（TMEM CT）在秀丽隐杆线虫神经元中的泛神经元表达驱动了一套疾病相关表型，有助于模拟TMEM106B神经病理学的分子和细胞特征。TMEM CT表达导致广泛的TMEM聚集和高度不溶性蛋白的积累。TMEM CT表达引起中度至重度神经元功能障碍，依赖于通过刻板行为读数测量的TMEM CT丰度。TMEM CT表达驱动显著的神经退行性改变。Dendra2标记的TMEM表现出与未标记的TMEM相似的特性，允许随时可视化蛋白质。TMEM CT聚集在溶酶体附近，但不在溶酶体内。PGRN功能丧失不影响TMEM CT毒性。tau和TDP - 43蛋白病变的修饰剂对TMEM CT相关的神经退行性表型几乎没有影响。

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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.