Several ALS-, FTD-, and IBM-causing mutations cause aberrant phase separation and change the biophysical and material properties of stress granules, generally resulting in poorly dynamic membrane-less organelles that, it has been suggested, may evolve into the cytoplasmic pathology found in end-stage disease ( Mackenzie et al., 2017 Buchan et al., 2013 Kim et al., 2013). Furthermore, pathological poly-dipeptides arising from repeat-expanded C9orf72, the most common genetic cause of ALS-FTD, insinuate into stress granules and other membrane-less organelles, perturbing their dynamics and/or functions ( Lee et al., 2016 Boeynaems et al., 2017). Another set of disease-causing mutations impact ubiquitin-binding proteins (e.g., UBQLN2, VCP, p62/SQSTM1, and OPTN) whose functions intersect with disassembly and/or clearance of stress granules ( Buchan et al., 2013 Dao et al., 2018 Chitiprolu et al., 2018). Furthermore, these mutations largely cluster in low-complexity, intrinsically disordered regions (IDRs) and in many cases have been shown to change the dynamic properties of stress granules ( Mackenzie et al., 2017 Hackman et al., 2013 Kim et al., 2013 Liu-Yesucevitz et al., 2010). Many mutations that cause ALS-FTD and/or IBM impact RNA-binding proteins that are building blocks of stress granules (e.g., TDP-43, hnRNPA1, hnRNPA2B1, hnRNPDL, TIA1, matrin 3, and FUS). A prominent feature of this end-stage cytoplasmic pathology is ubiquitinated and phosphorylated forms of TDP-43, although a host of other proteins co-localize with these pathological inclusions, including related RNA-binding proteins and ubiquitin-binding proteins such as SQSTM1, UBQLN2, OPTN, and VCP ( Neumann et al., 2006 Mackenzie et al., 2007 Mackenzie and Neumann, 2016 Williams et al., 2012 Deng et al., 2011). These diseases show substantial clinical and genetic overlap and share the hallmark histopathological feature of cytoplasmic inclusions composed of RNA-binding proteins and other constituents of ribonucleoprotein (RNP) granules in affected neurons and muscle cells.
Fus protein scaffold and client driver#
Genetic, pathologic, biophysical, and cell biological evidence has implicated disturbances in stress granules as a primary driver of several common neurodegenerative diseases, including ALS, FTD, and inclusion body myopathy (IBM) ( Molliex et al., 2015 Mackenzie et al., 2017 Taylor et al., 2016 Lee et al., 2016 Ramaswami et al., 2013 Buchan et al., 2013 Patel et al., 2015 Hackman et al., 2013). The Reviewing Editor's assessment is that all the issues have been addressed ( see decision letter).
Fus protein scaffold and client how to#
In this system, which permits experimental control of SGs in living cells in the absence of exogenous stressors, we demonstrate that persistent or repetitive assembly of SGs is cytotoxic and is accompanied by the evolution of SGs to cytoplasmic inclusions that recapitulate the pathology of ALS-FTD.Įditorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review.
Here we introduce a light-inducible SG system, termed OptoGranules, based on optogenetic multimerization of G3BP1, which is an essential scaffold protein for SG assembly. However, this concept has remained largely untestable in available models of SG assembly, which require the confounding variable of exogenous stressors. Disturbances in SG dynamics have been implicated as a primary driver of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), suggesting the hypothesis that these diseases reflect an underlying disturbance in the dynamics and material properties of SGs. Stress granules (SGs) are non-membrane-bound RNA-protein granules that assemble through phase separation in response to cellular stress.
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