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
TL;DR: Two possible disease-modifying therapies that can slow disease progression are available for ALS, but patient management is largely mediated by symptomatic therapies, such as the use of muscle relaxants for spasticity and speech therapy for dysarthria.
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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
Proteomic analyses reveal that loss of TDP-43 affects RNA processing and intracellular transport.
M. Stalekar,Xiaoke Yin,K. Rebolj,Simona Darovic,Claire Troakes,Manuel Mayr,Christopher Shaw,Boris Rogelj +7 more
TL;DR: It is shown that Ran-binding protein 1 (RanBP1), DNA methyltransferase 3 alpha (Dnmt3a) and chromogranin B (CgB) are downregulated upon TDP-43 knockdown, and transportin 1 level is increased as a result of RanBP1 depletion, suggesting that Improper regulation of these proteins and the subsequent disruption of cellular processes may play a role in the pathogenesis of the TSPs ALS and FTLD.
Journal ArticleDOI
Heat-shock protein dysregulation is associated with functional and pathological TDP-43 aggregation
TL;DR: The study suggests that a common mechanism could be involved in the pathogenesis of conformational diseases that result from HSP dysregulation, and suggests that the heat-shock protein (HSP)-90 inhibitor 17-AAG prevents ROS-induced TDP-43 aggregation, alters the type of T DP-43 multimers and reduces the severity of pathological TDP -43 inclusions.
Journal ArticleDOI
FUS-mediated alternative splicing in the nervous system: consequences for ALS and FTLD.
TL;DR: Gene ontology analysis of all putative targets unanimously suggests a role in axon growth and cytoskeletal organization, consistent with the altered morphology of dendritic spines and axonal growth cones reported upon loss of FUS.
Journal ArticleDOI
MicroRNAs: newcomers into the ALS picture.
TL;DR: The discovery of the involvement of ALS mutated proteins TDP43 and FUS/TLS in miRNAs biogenesis strongly suggests a role of miRNA dysregulation also in ALS and many efforts are thus directed toward understanding the role of these small RNA molecules in the pathogenesis of ALS.
Journal ArticleDOI
Regulation of MALAT1 expression by TDP43 controls the migration and invasion of non-small cell lung cancer cells in vitro.
TL;DR: It is demonstrated that MALAT1 expression by regulation of TDP-43 controls cellular growth, migration, and invasion of NSCLCs.
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