An optogenetic approach to establish the interplay between stress granules and TDP-43 proteinopathy in ALS/FTD

一种光遗传学方法来确定 ALS/FTD 中应激颗粒与 TDP-43 蛋白病之间的相互作用

基本信息

批准号：
10370344
负责人：
Christopher James Donnelly
金额：
$ 37.22万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-15 至 2023-02-28
项目状态：
已结题

项目摘要

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disorder marked by loss of motor neurons of the spinal cord and cortex. ALS is characterized by significant heterogeneity in disease onset and patient presentation. Over the last twenty years, mutations in over 35 different genes have been uncovered as causal in the development of familial forms of ALS (fALS); however, fALS only accounts for roughly 10% of all ALS cases. The remaining 90% of patients suffer from sporadic ALS (sALS), with no family history of disease and unknown causes of pathogenesis. Regardless of all this genetic and pathogenic complexity, remarkably nearly every single ALS patient (both fALS and sALS) share a common neuropathology in the form of aberrant cytoplasmic inclusions of a protein called TAR DNA-binding protein of 43 kDa (TDP-43) found in degenerating regions of the nervous system. Insight drawn from studies of fALS-linked mutations have implicated stress granule dysfunction in disease development, but the exact mechanisms by which the stress granules may directly regulate TDP-43 aggregation remains unclear. By utilizing a novel optogenetic approach to induce either TDP-43 inclusions or functional stress granules, we can manipulate these processes at a previously unattainable level of control. These experiments will explore the contribution of stress granule dysfunction to TDP-43 inclusion neurotoxicity. We hypothesize that perturbations in stress granule dynamics contribute to neurotoxic TDP-43 aggregation in ALS. We will first investigate the contribution of stress granules to light-induced TDP-43 inclusions. We will then determine if chronic or persistent stress granule formation initiates TDP-43 proteinopathy. Finally, we will perform a genome-wide RNAi screen to identify novel pathways that protect against TDP-43 inclusion toxicity and assess whether this protection is dependent on stress granule regulation.

肌萎缩性外侧硬化症（ALS）是一种进行性的致命神经退行性疾病。通过脊髓和皮质的运动神经元的丧失。 ALS的特征是疾病发作和患者表现的异质性。在过去的二十年中，突变在超过35种不同的基因中，已经发现了家族形式发展的因果 ALS（fals）；但是，伪造仅占所有ALS案件的10％。其余 90％的患者患有零星ALS（SALS），没有疾病的家族史和未知的家族病史发病机理的原因。不管所有这些遗传和致病性复杂性，都非常明显在一种称为TAR DNA结合蛋白为43 kDa的蛋白质的异常细胞质夹杂物的形式（TDP-43）在神经系统的退化区域中发现。从研究中得出的见解伪造的突变已暗示疾病发育中的应力颗粒功能障碍，但应力颗粒可以直接调节TDP-43聚集的确切机制仍然不清楚。通过利用一种新型的光遗传学方法诱导TDP-43夹杂物或功能应力颗粒，我们可以在先前无法实现的情况下操纵这些过程控制水平。这些实验将探讨应力颗粒功能障碍对 TDP-43包容性神经毒性。我们假设应力颗粒动力学中的扰动在ALS中有助于神经毒性TDP-43聚集。我们将首先调查应力颗粒对光诱导的TDP-43夹杂物。然后，我们将确定是慢性还是持续的应激颗粒形成启动TDP-43蛋白质病。最后，我们将执行全基因组RNAi屏幕以识别防止TDP-43包含的新型途径毒性并评估该保护是否取决于压力颗粒调节。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Nuclear import receptors are recruited by FG-nucleoporins to rescue hallmarks of TDP-43 proteinopathy.

DOI：
10.1186/s13024-022-00585-1
发表时间：
2022-12-08
期刊：
Molecular neurodegeneration
影响因子：
15.1
作者：
通讯作者：

NUP62 localizes to ALS/FTLD pathological assemblies and contributes to TDP-43 insolubility.

DOI：
10.1038/s41467-022-31098-6
发表时间：
2022-06-13
期刊：
Nature communications
影响因子：
16.6
作者：
通讯作者：

Traumatic injury compromises nucleocytoplasmic transport and leads to TDP-43 pathology.

DOI：
10.7554/elife.67587
发表时间：
2021-05-26
期刊：
eLife
影响因子：
7.7
作者：
Anderson EN;Morera AA;Kour S;Cherry JD;Ramesh N;Gleixner A;Schwartz JC;Ebmeier C;Old W;Donnelly CJ;Cheng JP;Kline AE;Kofler J;Stein TD;Pandey UB
通讯作者：
Pandey UB

Optogenetic TDP-43 nucleation induces persistent insoluble species and progressive motor dysfunction in vivo.

DOI：
10.1016/j.nbd.2020.105078
发表时间：
2020-12
期刊：
NEUROBIOLOGY OF DISEASE
影响因子：
6.1
作者：
Otte, Charlton G.;Fortuna, Tyler R.;Mann, Jacob R.;Gleixner, Amanda M.;Ramesh, Nandini;Pyles, Noah J.;Pandey, Udai B.;Donnelly, Christopher J.
通讯作者：
Donnelly, Christopher J.

Local translation in primary afferents and its contribution to pain.