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
TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia
TL;DR: TDP-43 and FUS are promising candidates for the development of novel biomarker assays and targeted therapies because of the striking functional and structural similarities of these proteins, which imply that abnormal RNA metabolism is a pivotal event in neurodegeneration.
Journal ArticleDOI
Stress granules as crucibles of ALS pathogenesis
TL;DR: This work has shown that TDP-43 and FUS and several related RNA-binding proteins harbor aggregation-promoting prion-like domains that allow them to rapidly self-associate, critical for the formation and dynamics of cellular ribonucleoprotein granules, the crucibles of RNA metabolism and homeostasis.
Journal ArticleDOI
ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import
Dorothee Dormann,Dorothee Dormann,Ramona Rodde,Ramona Rodde,Dieter Edbauer,Eva Bentmann,Eva Bentmann,Ingeborg Fischer,Alexander Hruscha,Manuel E Than,Ian R. A. Mackenzie,Anja Capell,Anja Capell,Bettina Schmid,Manuela Neumann,Christian Haass,Christian Haass +16 more
TL;DR: It is proposed that two pathological hits, namely nuclear import defects and cellular stress, are involved in the pathogenesis of FUS‐opathies.
Journal ArticleDOI
TDP-43 Is Intrinsically Aggregation-prone, and Amyotrophic Lateral Sclerosis-linked Mutations Accelerate Aggregation and Increase Toxicity
Brian S. Johnson,David Snead,Jonathan Lee,J. Michael McCaffery,James Shorter,Aaron D. Gitler +5 more
TL;DR: It is reported that, in the absence of other components, TDP-43 spontaneously forms aggregates bearing remarkable ultrastructural similarities to TDP -43 deposits in degenerating neurons of ALS FTLD-U patients.
Journal ArticleDOI
A new subtype of frontotemporal lobar degeneration with FUS pathology.
Manuela Neumann,Rosa Rademakers,Sigrun Roeber,Matt Baker,Hans A. Kretzschmar,Ian R. A. Mackenzie +5 more
TL;DR: Findings suggest that FUS is the pathological protein in a significant subgroup of sporadic FTD and reinforce the concept that FTd and amyotrophic lateral sclerosis are closely related conditions.
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