The debated toxic role of aggregated TDP-43 in amyotrophic lateral sclerosis: a resolution in sight?
Rudolf Hergesheimer,Anna A. Chami,Denis Reis de Assis,Patrick Vourc'h,Christian R. Andres,Philippe Corcia,Débora Lanznaster,Hélène Blasco +7 more
TLDR
It is concluded that TDP-43 aggregation is a major factor in neuronal death in ALS, with potential therapeutic implications, and Hergesheimer et al.Abstract:
Transactive response DNA-binding protein-43 (TDP-43) is an RNA/DNA binding protein that forms phosphorylated and ubiquitinated aggregates in the cytoplasm of motor neurons in amyotrophic lateral sclerosis, which is a hallmark of this disease. Amyotrophic lateral sclerosis is a neurodegenerative condition affecting the upper and lower motor neurons. Even though the aggregative property of TDP-43 is considered a cornerstone of amyotrophic lateral sclerosis, there has been major controversy regarding the functional link between TDP-43 aggregates and cell death. In this review, we attempt to reconcile the current literature surrounding this debate by discussing the results and limitations of the published data relating TDP-43 aggregates to cytotoxicity, as well as therapeutic perspectives of TDP-43 aggregate clearance. We point out key data suggesting that the formation of TDP-43 aggregates and the capacity to self-template and propagate among cells as a 'prion-like' protein, another pathological property of TDP-43 aggregates, are a significant cause of motor neuronal death. We discuss the disparities among the various studies, particularly with respect to the type of models and the different forms of TDP-43 used to evaluate cellular toxicity. We also examine how these disparities can interfere with the interpretation of the results pertaining to a direct toxic effect of TDP-43 aggregates. Furthermore, we present perspectives for improving models in order to better uncover the toxic role of aggregated TDP-43. Finally, we review the recent studies on the enhancement of the cellular clearance mechanisms of autophagy, the ubiquitin proteasome system, and endocytosis in an attempt to counteract TDP-43 aggregation-induced toxicity. Altogether, the data available so far encourage us to suggest that the cytoplasmic aggregation of TDP-43 is key for the neurodegeneration observed in motor neurons in patients with amyotrophic lateral sclerosis. The corresponding findings provide novel avenues toward early therapeutic interventions and clinical outcomes for amyotrophic lateral sclerosis management.read more
Citations
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Phase Separation and Neurodegenerative Diseases: A Disturbance in the Force.
TL;DR: The authors reviewed similarities and differences among four main proteins, α-synuclein, FUS, tau, and TDP-43, which are found aggregated in different diseases and were independently shown to phase separate.
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The role of TDP-43 mislocalization in amyotrophic lateral sclerosis
TL;DR: The theme of protein mislocalization as a key mechanism underlying ALS is brought forth, by highlighting the importance of maintaining subcellular proteostasis along with the gain- and loss-of-functional consequences when TDP-43 localization is dysregulated.
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The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
Yevgeniya Abramzon,Yevgeniya Abramzon,Pietro Fratta,Bryan J. Traynor,Bryan J. Traynor,Ruth Chia +5 more
TL;DR: A summary of the significant genes identified in these two intrinsically linked neurodegenerative diseases and highlight the genetic and pathological overlaps is provided.
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Transposable Elements, Inflammation, and Neurological Disease
TL;DR: It is postulate that active mobile genetic elements contribute more to human disease pathogenesis than previously thought.
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Do Post-Translational Modifications Influence Protein Aggregation in Neurodegenerative Diseases: A Systematic Review.
TL;DR: It is identified that the following PTMs, in isolation or combination, potentially act as modulators of proteinopathy in NDDs: isoaspartate formation in Aβ, phosphorylation of Aβ or tau in AD, acetylation, 4-hydroxy-2-neonal modification, O-GlcNAcylation or phosphorylated of α-synuclein in PD, and SUMOylation of superoxide dismutase-1 in ALS.
References
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Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Manuela Neumann,Deepak M. Sampathu,Linda K. Kwong,Adam C. Truax,Matthew Micsenyi,Thomas T. Chou,Jennifer Bruce,Theresa Schuck,Murray Grossman,Christopher M. Clark,Leo McCluskey,Bruce L. Miller,Eliezer Masliah,Ian R. A. Mackenzie,Howard Feldman,Wolfgang Feiden,Hans A. Kretzschmar,John Q. Trojanowski,Virginia M.-Y. Lee +18 more
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Journal ArticleDOI
TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis
Jemeen Sreedharan,Ian P. Blair,Vineeta B. Tripathi,Xun Hu,Caroline Vance,Boris Rogelj,Steven Ackerley,Steven Ackerley,Jennifer C Durnall,Kelly L. Williams,Emanuele Buratti,Francisco E. Baralle,Jacqueline de Belleroche,J. Douglas Mitchell,P. Nigel Leigh,Ammar Al-Chalabi,Christopher C.J. Miller,Christopher C.J. Miller,Garth A. Nicholson,Garth A. Nicholson,Christopher Shaw +20 more
TL;DR: The evidence suggests a pathophysiological link between TDP-43 and ALS, and neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases.
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Mutations in FUS, an RNA Processing Protein, Cause Familial Amyotrophic Lateral Sclerosis Type 6
Caroline Vance,Boris Rogelj,Tibor Hortobágyi,Kurt J. De Vos,Agnes L. Nishimura,Jemeen Sreedharan,Xun Hu,Bradley N. Smith,Deborah Ruddy,Paul Wright,Jeban Ganesalingam,Kelly L. Williams,Vineeta B. Tripathi,Safa Al-Saraj,Ammar Al-Chalabi,P. Nigel Leigh,Ian P. Blair,Garth A. Nicholson,Garth A. Nicholson,Jackie de Belleroche,Jean-Marc Gallo,Christopher C.J. Miller,Christopher C.J. Miller,Christopher Shaw +23 more
TL;DR: A missense mutation in the gene encoding fused in sarcoma (FUS) in a British kindred, linked to ALS6, is identified, which suggests that a common mechanism may underlie motor neuron degeneration.
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TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Tetsuaki Arai,Masato Hasegawa,Haruhiko Akiyama,Kenji Ikeda,Takashi Nonaka,Hiroshi Mori,David M. A. Mann,Kuniaki Tsuchiya,Mari Yoshida,Yoshio Hashizume,Tatsuro Oda +10 more
TL;DR: The common occurrence of intracellular accumulations of TDP-43 supports the hypothesis that these disorders represent a clinicopathological entity of a single disease, and suggests that they can be newly classified as a proteinopathy of T DP-43.
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The roles of intracellular protein-degradation pathways in neurodegeneration
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