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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Rita Mejzini,Loren L. Flynn,Loren L. Flynn,Ianthe Pitout,Ianthe Pitout,Sue Fletcher,Sue Fletcher,Steve D. Wilton,Steve D. Wilton,P.A. Akkari,P.A. Akkari +10 more
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.
Journal ArticleDOI
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
Arginine methylation next to the PY‐NLS modulates Transportin binding and nuclear import of FUS
Dorothee Dormann,Tobias Madl,Tobias Madl,Chiara F. Valori,Chiara F. Valori,Eva Bentmann,Sabina Tahirovic,Claudia Abou-Ajram,Elisabeth Kremmer,Olaf Ansorge,Ian R. A. Mackenzie,Manuela Neumann,Manuela Neumann,Manuela Neumann,Christian Haass,Christian Haass +15 more
TL;DR: This study shows that arginine methylation modulates nuclear import of FUS via a novel TRN‐binding epitope and provides evidence that these two diseases may be initiated by distinct pathomechanisms and implicates alterations in arginin methylation in pathogenesis.
Journal Article
An RNA-binding Protein Gene, TLS/FUS , Is Fused to ERG in Human Myeloid Leukemia with t(16;21) Chromosomal Translocation
TL;DR: The TLS/FUS-ERG gene fusion in t(16;21) leukemia is predicted to produce a protein that is very similar to the EWS-ERG chimeric protein responsible for Ewing's sarcoma.
Journal ArticleDOI
The role of FUS gene variants in neurodegenerative diseases
Hao Deng,Kai Gao,Joseph Jankovic +2 more
TL;DR: Current understanding of the normal function of FUS is summarized, its role in the pathology of ALS, FTLD, essential tremor and other neurodegenerative diseases is described, and comments on the underlying pathogenetic mechanisms are included.
Journal ArticleDOI
Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions.
Johnathan Cooper-Knock,Matthew J. Walsh,Adrian Higginbottom,J. Robin Highley,Mark J. Dickman,Dieter Edbauer,Paul G. Ince,Stephen B. Wharton,Stuart A. Wilson,Janine Kirby,Guillaume M. Hautbergue,Pamela J. Shaw +11 more
TL;DR: Using RNA pulldown and immunohistochemistry in ALS biosamples, Cooper-Knock et al. identify proteins that bind to the repeat expansions in C9orf72 that cause familial amyotrophic lateral sclerosis and frontotemporal dementia.
Journal ArticleDOI
FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations.
Manuela Neumann,Eva Bentmann,Dorothee Dormann,Ali Jawaid,Mariely DeJesus-Hernandez,Olaf Ansorge,Sigrun Roeber,Hans A. Kretzschmar,David G. Munoz,Hirofumi Kusaka,Osamu Yokota,Lee Cyn Ang,Juan M. Bilbao,Rosa Rademakers,Christian Haass,Ian R. A. Mackenzie +15 more
TL;DR: Data imply different pathological processes underlying inclusion formation and cell death between both conditions; the pathogenesis in amyotrophic lateral sclerosis with FUS mutations appears to be more restricted to dysfunction of fused in sarcoma, while a more global and complex dysregulation of all FET proteins is involved in the subtypes of frontotemporal lobar degeneration with fused in Sarcoma pathology.
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