Loss of Dynamic RNA Interaction and Aberrant Phase Separation Induced by Two Distinct Types of ALS/FTD-Linked FUS Mutations

Niaki, Amirhossein Ghanbari; Sarkar, Jaya; Cai, Xinyi; Rhine, Kevin; Vidaurre, Velinda; Guy, Brian; Hurst, Miranda N; Lee, Jong Chan; Koh, Hye Ran; Guo, Lin; Fare, Charlotte M.; Shorter, James; Myong, Sua

doi:10.1016/j.molcel.2019.09.022

Cited by 136 publications

(174 citation statements)

References 53 publications

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“…It is now established that LLPS is modulated by universal cellular actors such as ATP and nucleic acids through enhancement and dissolution (Kang et al, 2019). Other recent FUS studies expanded on LLPS functions, mechanism, and transformation (Berry et al, 2018;Kang et al, 2019;Murthy et al, 2019;Niaki et al, 2019).…”

Section: Fused In Sarcoma (Fus)mentioning

confidence: 99%

The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

et al. 2020

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two diseases that form a broad neurodegenerative continuum. Considerable effort has been made to unravel the genetics of these disorders, and, based on this work, it is now clear that ALS and FTD have a significant genetic overlap. TARDBP, SQSTM1, VCP, FUS, TBK1, CHCHD10, and most importantly C9orf72, are the critical genetic players in these neurological disorders. Discoveries of these genes have implicated autophagy, RNA regulation, and vesicle and inclusion formation as the central pathways involved in neurodegeneration. Here we provide a summary of the significant genes identified in these two intrinsically linked neurodegenerative diseases and highlight the genetic and pathological overlaps.

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Section: Fused In Sarcoma (Fus)mentioning

confidence: 99%

The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

et al. 2020

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“…Metazoa may partially compensate for the absence of Hsp104 activity in the cytoplasm and nucleus with alternative general protein-disaggregase systems, such as Hsp110, Hsp70, Hsp40, and small heat-shock proteins ( Duennwald et al, 2012 ; Mattoo et al, 2013 ; Nillegoda et al, 2015 ; Scior et al, 2018 ; Shorter, 2011 ; Shorter, 2017 ; Torrente and Shorter, 2013 ) as well as client-specific disaggregases in the cytoplasm such as nuclear-import receptors ( Guo et al, 2019 ; Guo et al, 2018 ; Niaki et al, 2020 ; Yoshizawa et al, 2018 ). However, Hsp110 is not found in mitochondria ( Voos and Röttgers, 2002 ).…”

Section: Introductionmentioning

confidence: 99%

Skd3 (human ClpB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations

Cupo

Shorter

2020

eLife

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202

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Cells have evolved specialized protein disaggregases to reverse toxic protein aggregation and restore protein functionality. In nonmetazoan eukaryotes, the AAA+ disaggregase Hsp78 resolubilizes and reactivates proteins in mitochondria. Curiously, metazoa lack Hsp78. Hence, whether metazoan mitochondria reactivate aggregated proteins is unknown. Here, we establish that a mitochondrial AAA+ protein, Skd3 (human ClpB), couples ATP hydrolysis to protein disaggregation and reactivation. The Skd3 ankyrin-repeat domain combines with conserved AAA+ elements to enable stand-alone disaggregase activity. A mitochondrial inner-membrane protease, PARL, removes an autoinhibitory peptide from Skd3 to greatly enhance disaggregase activity. Indeed, PARL-activated Skd3 solubilizes α-synuclein fibrils connected to Parkinson’s disease. Human cells lacking Skd3 exhibit reduced solubility of various mitochondrial proteins, including anti-apoptotic Hax1. Importantly, Skd3 variants linked to 3-methylglutaconic aciduria, a severe mitochondrial disorder, display diminished disaggregase activity (but not always reduced ATPase activity), which predicts disease severity. Thus, Skd3 is a potent protein disaggregase critical for human health.

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“…To gain mechanistic insight into the G4 resolving activity of three helicases, we examined the smFRET traces taken in real-time flow measurements in which data were acquired while the protein and ATP were added to the G4-containing DNA substrate. This experiment provides insights into all stages of the protein activity in one contiguous movie ( 25 , 50 , 51 ). The four stages include (I) helicase loading, (II) G4 unfolding, (III) duplex unwinding and (IV) completion of unwinding (Figure 3A ).…”

Section: Resultsmentioning

confidence: 99%

E. coli Rep helicase and RecA recombinase unwind G4 DNA and are important for resistance to G4-stabilizing ligands

Paul

Voter

Cueny

et al. 2020

Nucleic Acids Research

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Abstract G-quadruplex (G4) DNA structures can form physical barriers within the genome that must be unwound to ensure cellular genomic integrity. Here, we report unanticipated roles for the Escherichia coli Rep helicase and RecA recombinase in tolerating toxicity induced by G4-stabilizing ligands in vivo. We demonstrate that Rep and Rep-X (an enhanced version of Rep) display G4 unwinding activities in vitro that are significantly higher than the closely related UvrD helicase. G4 unwinding mediated by Rep involves repetitive cycles of G4 unfolding and refolding fueled by ATP hydrolysis. Rep-X and Rep also dislodge G4-stabilizing ligands, in agreement with our in vivo G4-ligand sensitivity result. We further demonstrate that RecA filaments disrupt G4 structures and remove G4 ligands in vitro, consistent with its role in countering cellular toxicity of G4-stabilizing ligands. Together, our study reveals novel genome caretaking functions for Rep and RecA in resolving deleterious G4 structures.

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Loss of Dynamic RNA Interaction and Aberrant Phase Separation Induced by Two Distinct Types of ALS/FTD-Linked FUS Mutations

Cited by 136 publications

References 53 publications

The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Skd3 (human ClpB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations

E. coli Rep helicase and RecA recombinase unwind G4 DNA and are important for resistance to G4-stabilizing ligands

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