Journal ArticleDOI
Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins
Antonia Ratti,Emanuele Buratti +1 more
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TLDR
The aim of this review will be to provide a general overview of TDP‐43 and FUS/TLS proteins and to highlight their physiological functions.Abstract:
The multiple roles played by RNA binding proteins in neurodegeneration have become apparent following the discovery of TAR DNA binding protein 43 kDa (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS) involvement in amyotrophic lateral sclerosis and frontotemporal lobar dementia. In these two diseases, the majority of patients display the presence of aggregated forms of one of these proteins in their brains. The study of their functional properties currently represents a very promising target for developing the effective therapeutic options that are still lacking. This aim, however, must be preceded by an accurate evaluation of TDP-43 and FUS/TLS biological functions, both in physiological and disease conditions. Recent findings have uncovered several aspects of RNA metabolism that can be affected by misregulation of these two proteins. Progress has also been made in starting to understand how the aggregation of these proteins occurs and spreads from cell to cell. The aim of this review will be to provide a general overview of TDP-43 and FUS/TLS proteins and to highlight their physiological functions. At present, the emerging picture is that TDP-43 and FUS/TLS control several aspects of an mRNA's life, but they can also participate in DNA repair processes and in non-coding RNA metabolism. Although their regulatory activities are similar, they regulate mainly distinct RNA targets and show different pathogenetic mechanisms in amyotrophic lateral sclerosis/frontotemporal lobar dementia diseases. The identification of key events in these processes represents today the best chance of finding targetable options for therapeutic approaches that might actually make a difference at the clinical level. The two major RNA Binding Proteins involved in Amyotrophic Lateral Sclerosisi and Frontotemporal Dementia are TDP-43 and FUST/TLS. Both proteins are involved in regulating all aspects of RNA and RNA life cycle within neurons, from transcription, processing, and transport/stability to the formation of cytoplasmic and nuclear stress granules. For this reason, the aberrant aggregation of these factors during disease can impair multiple RNA metabolic pathways and eventually lead to neuronal death/inactivation. The purpose of this review is to provide an up-to-date perspective on what we know about this issue at the molecular level. This article is part of the Frontotemporal Dementia special issue.read more
Citations
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Journal ArticleDOI
Pathology of Neurodegenerative Diseases
TL;DR: This review details the human pathology of select neurodegenerative disorders, focusing on their main protein aggregates, and suggests that abnormal protein conformers may spread from cell to cell along anatomically connected pathways.
Journal ArticleDOI
Amyotrophic lateral sclerosis
Eva L. Feldman,Stephen A. Goutman,Susanne Petri,Letizia Mazzini,Masha G. Savelieff,Pamela J. Shaw,Gen Sobue +6 more
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TL;DR: The genetic basis of ALS is reviewed, highlighting factors that have contributed to the elusiveness of genetic heritability and future directions for research that may lead to effective treatment strategies outlined.
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Genetic mutations in RNA-binding proteins and their roles in ALS
TL;DR: This work focuses on several key RBPs involved in ALS—TDP-43, H NRNP A2/B1, HNRNP A1, FUS, EWSR1, and TAF15—and review the current understanding of how mutations in these proteins cause disease.
Journal ArticleDOI
TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response
Peng Wang,Jianwen Deng,Jie Dong,Jianghong Liu,Eileen H. Bigio,M.-Marsel Mesulam,Tao Wang,Lei Sun,Li Wang,Alan Yueh Luen Lee,Warren A. McGee,Xiaoping Chen,Kazuo Fushimi,Li Zhu,Jane Y. Wu,Jane Y. Wu +15 more
TL;DR: It is suggested that blocking or reversing mitochondrial damage may provide a potential therapeutic approach to these devastating diseases and uncovered a previously unknown role of LonP1 in regulating mitochondrial TDP-43 levels, but also advanced the understanding of the pathogenic mechanisms for T DP-43 proteinopathy.
References
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Journal ArticleDOI
Delineation of the core aggregation sequences of TDP-43 C-terminal fragment.
Akash Saini,Virander S. Chauhan +1 more
TL;DR: This study employed a set of synthetic peptides spanning the length of the TDP‐43 CTF in order to find out its core aggregation domains, and identifies two regions, one in the RRM‐2 domain and the other in the C‐terminal domain, that stand out as highly aggregation prone.
Journal ArticleDOI
Protein arginine methyltransferase 1 and 8 interact with FUS to modify its sub-cellular distribution and toxicity in vitro and in vivo.
Chiara Scaramuzzino,John Monaghan,Carmelo Milioto,Nicholas A. Lanson,Astha Maltare,Tanya Aggarwal,Ian Casci,Frank O. Fackelmayer,Maria Pennuto,Udai Bhan Pandey +9 more
TL;DR: It is found that wild type FUS (FUS-WT) specifically interacts with protein arginine methyltransferases 1 and 8 (PRMT1 and PRMT8) and undergoes asymmetric dimethylation in cultured cells, which support a role for arkinine methylation in the pathogenesis of FUS-related ALS.
Journal ArticleDOI
U1 snRNP is mislocalized in ALS patient fibroblasts bearing NLS mutations in FUS and is required for motor neuron outgrowth in zebrafish
Yong Yu,Binkai Chi,Wei Xia,Jaya Gangopadhyay,Tomohiro Yamazaki,Marlene E. Winkelbauer-Hurt,Shanye Yin,Yoan Eliasse,Eddie W. Adams,Christopher Shaw,Robin Reed +10 more
TL;DR: Linking an essential canonical splicing factor (U1 snRNP) to this pathway provides strong new evidence that splicing defects may be involved in pathogenesis and that this pathway is a potential therapeutic target.
Journal ArticleDOI
Neurodegeneration the RNA way.
Abigail J. Renoux,Peter K. Todd +1 more
TL;DR: This work discusses a set of "RNAopathies", where non-coding repeat expansions drive pathogenesis through a surprisingly diverse set of mechanisms, and explores an emerging class of " RNA binding proteinopathies" where redistribution and aggregation of the RNA binding proteins TDP-43 or FUS contribute to a potentially broad range of neurodegenerative disorders.
Journal ArticleDOI
Review: Prion-like mechanisms of transactive response DNA binding protein of 43 kDa (TDP-43) in amyotrophic lateral sclerosis (ALS)
TL;DR: The prion‐like mechanisms of TDP‐43 are compared to the clinical and biological nature of ALS in order to investigate how this protein could be responsible for some of the characteristic properties of the disease.
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