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Understanding TDP-43-Mediated Mechanisms in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 33363

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Special Issue Editors

Dr. Yazi Ke

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Guest Editor

Dementia Research Centre, Macquarie University, NSW 2109, Australia
Interests: frontotemporal dementia; amyotrophic lateral sclerosis; animal models; protein-protein interactions; disease mechanisms

Dr. Adam K. Walker

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Co-Guest Editor

Neurodegeneration Pathobiology Laboratory, Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia

Special Issue Information

Dear Colleagues,

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are rapidly progressing fatal neurodegenerative diseases with no effective treatments. While most ALS cases are sporadic, mutations in several genes such as TARDBP, C9ORF72, SOD1, FUS have been identified over the years in familial ALS cases. FTD and ALS are part of a disease continuum and share a neuropathology containing cytoplasmic inclusions of the TAR DNA-binding protein 43 (TDP-43) which is found in >90% of ALS and ~50% of FTD cases. This strongly suggests the pivotal role that TDP-43 plays in disease pathology. Understanding the physiological and pathological role of TDP-43 in disease initiation and progression will aid us in identifying alternative treatment options.

This Special Issue, “Understanding TDP-43-Mediated Mechanisms in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis”, will cover a wide selection of research topics and review articles in the field of FTD and ALS, looking at various aspects of TDP-43’s role in disease with a special focus on TDP-43-mediated mechanisms. Original research articles, reviews, commentaries, and perspectives are all welcomed.

Dr. Yazi Ke
Dr. Adam K. Walker
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

TDP-43
disease mechanisms
Frontotemporal dementia
Amyotrophic lateral sclerosis
protein–protein interactions
cellular functions

Published Papers (6 papers)

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Research

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18 pages, 4688 KiB

Open AccessArticle

Cell Stress Induces Mislocalization of Transcription Factors with Mitochondrial Enrichment

by Chiara Rossi, Anna Fernàndez, Pascual Torres, Omar Ramirez-Nuñez, Ana Belén Granado-Serrano, Laia Fontdevila, Mònica Povedano, Reinald Pamplona, Isidro Ferrer and Manuel Portero-Otin

Int. J. Mol. Sci. 2021, 22(16), 8853; https://doi.org/10.3390/ijms22168853 - 17 Aug 2021

Cited by 4 | Viewed by 2343

Abstract

Previous evidence links the formation of extranuclear inclusions of transcription factors, such as ERK, Jun, TDP-43, and REST, with oxidative, endoplasmic-reticulum, proteasomal, and osmotic stress. To further characterize its extranuclear location, we performed a high-content screening based on confocal microscopy and automatized image analyses of an epithelial cell culture treated with hydrogen peroxide, thapsigargin, epoxomicin, or sorbitol at different concentrations and times to recreate the stresses mentioned above. We also performed a subcellular fractionation of the brain from transgenic mice overexpressing the Q331K-mutated TARDBP, and we analyzed the REST-regulated mRNAs. The results show that these nuclear proteins exhibit a mitochondrial location, together with significant nuclear/extranuclear ratio changes, in a protein and stress-specific manner. The presence of these proteins in enriched mitochondrial fractions in vivo confirmed the results of the image analyses. TDP-43 aggregation was associated with alterations in the mRNA levels of the REST target genes involved in calcium homeostasis, apoptosis, and metabolism. In conclusion, cell stress increased the mitochondrial translocation of nuclear proteins, increasing the chance of proteostasis alterations. Furthermore, TDP-43 aggregation impacts REST target genes, disclosing an exciting interaction between these two transcription factors in neurodegenerative processes. Full article

(This article belongs to the Special Issue Understanding TDP-43-Mediated Mechanisms in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis)

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Review

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16 pages, 1272 KiB

Open AccessReview

The Different Faces of the TDP-43 Low-Complexity Domain: The Formation of Liquid Droplets and Amyloid Fibrils

by Hung-Ming Chien, Chi-Chang Lee and Joseph Jen-Tse Huang

Int. J. Mol. Sci. 2021, 22(15), 8213; https://doi.org/10.3390/ijms22158213 - 30 Jul 2021

Cited by 7 | Viewed by 4464

Abstract

Transactive response DNA-binding protein 43 (TDP-43) is a nucleic acid-binding protein that is involved in transcription and translation regulation, non-coding RNA processing, and stress granule assembly. Aside from its multiple functions, it is also known as the signature protein in the hallmark inclusions of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) patients. TDP-43 is built of four domains, but its low-complexity domain (LCD) has become an intense research focus that brings to light its possible role in TDP-43 functions and involvement in the pathogenesis of these neurodegenerative diseases. Recent endeavors have further uncovered the distinct biophysical properties of TDP-43 under various circumstances. In this review, we summarize the multiple structural and biochemical properties of LCD in either promoting the liquid droplets or inducing fibrillar aggregates. We also revisit the roles of the LCD in paraspeckles, stress granules, and cytoplasmic inclusions to date. Full article

(This article belongs to the Special Issue Understanding TDP-43-Mediated Mechanisms in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis)

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25 pages, 1202 KiB

Open AccessReview

TDP-43 and Inflammation: Implications for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

by Fiona Bright, Gabriella Chan, Annika van Hummel, Lars M. Ittner and Yazi D. Ke

Int. J. Mol. Sci. 2021, 22(15), 7781; https://doi.org/10.3390/ijms22157781 - 21 Jul 2021

Cited by 24 | Viewed by 6933

Abstract

The abnormal mislocalisation and ubiquitinated protein aggregation of the TAR DNA binding protein 43 (TDP-43) within the cytoplasm of neurons and glia in the central nervous system (CNS) is a pathological hallmark of early-onset neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The pathomechanisms underlying abnormal mislocalisation and aggregation of TDP-43 remain unknown. However, there is a growing body of evidence implicating neuroinflammation and immune-mediated mechanisms in the pathogenesis of neurodegeneration. Importantly, most of the evidence for an active role of immunity and inflammation in the pathogenesis of ALS and FTD relates specifically to TDP-43, posing the question as to whether immune-mediated mechanisms could hold the key to understanding TDP-43’s underlying role in neurodegeneration in both diseases. Therefore, this review aims to piece together key lines of evidence for the specific association of TDP-43 with key immune and inflammatory pathways to explore the nature of this relationship and the implications for potential pathomechanisms underlying neurodegeneration in ALS and FTD. Full article

(This article belongs to the Special Issue Understanding TDP-43-Mediated Mechanisms in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis)

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16 pages, 671 KiB

Open AccessReview

Mechanisms of TDP-43 Proteinopathy Onset and Propagation

by Han-Jou Chen and Jacqueline C. Mitchell

Int. J. Mol. Sci. 2021, 22(11), 6004; https://doi.org/10.3390/ijms22116004 - 02 Jun 2021

Cited by 9 | Viewed by 7084

Abstract

TDP-43 is an RNA-binding protein that has been robustly linked to the pathogenesis of a number of neurodegenerative disorders, including amyotrophic lateral sclerosis and frontotemporal dementia. While mutations in the TARDBP gene that codes for the protein have been identified as causing disease in a small subset of patients, TDP-43 proteinopathy is present in the majority of cases regardless of mutation status. This raises key questions regarding the mechanisms by which TDP-43 proteinopathy arises and spreads throughout the central nervous system. Numerous studies have explored the role of a variety of cellular functions on the disease process, and nucleocytoplasmic transport, protein homeostasis, RNA interactions and cellular stress have all risen to the forefront as possible contributors to the initiation of TDP-43 pathogenesis. There is also a small but growing body of evidence suggesting that aggregation-prone TDP-43 can recruit physiological TDP-43, and be transmitted intercellularly, providing a mechanism whereby small-scale proteinopathy spreads from cell to cell, reflecting the spread of clinical symptoms observed in patients. This review will discuss the potential role of the aforementioned cellular functions in TDP-43 pathogenesis, and explore how aberrant pathology may spread, and result in a feed-forward cascade effect, leading to robust TDP-43 proteinopathy and disease. Full article

(This article belongs to the Special Issue Understanding TDP-43-Mediated Mechanisms in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis)

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34 pages, 1532 KiB

Open AccessReview

Molecular Mechanisms Underlying TDP-43 Pathology in Cellular and Animal Models of ALS and FTLD

by Alistair Wood, Yuval Gurfinkel, Nicole Polain, Wesley Lamont and Sarah Lyn Rea

Int. J. Mol. Sci. 2021, 22(9), 4705; https://doi.org/10.3390/ijms22094705 - 29 Apr 2021

Cited by 45 | Viewed by 6482

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders that exist on a disease spectrum due to pathological, clinical and genetic overlap. In up to 97% of ALS cases and ~50% of FTLD cases, the primary pathological protein observed in affected tissues is TDP-43, which is hyperphosphorylated, ubiquitinated and cleaved. The TDP-43 is observed in aggregates that are abnormally located in the cytoplasm. The pathogenicity of TDP-43 cytoplasmic aggregates may be linked with both a loss of nuclear function and a gain of toxic functions. The cellular processes involved in ALS and FTLD disease pathogenesis include changes to RNA splicing, abnormal stress granules, mitochondrial dysfunction, impairments to axonal transport and autophagy, abnormal neuromuscular junctions, endoplasmic reticulum stress and the subsequent induction of the unfolded protein response. Here, we review and discuss the evidence for alterations to these processes that have been reported in cellular and animal models of TDP-43 proteinopathy. Full article

(This article belongs to the Special Issue Understanding TDP-43-Mediated Mechanisms in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis)

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17 pages, 8812 KiB

Open AccessReview

Pathway from TDP-43-Related Pathology to Neuronal Dysfunction in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration

by Yuichi Riku, Danielle Seilhean, Charles Duyckaerts, Susana Boluda, Yohei Iguchi, Shinsuke Ishigaki, Yasushi Iwasaki, Mari Yoshida, Gen Sobue and Masahisa Katsuno

Int. J. Mol. Sci. 2021, 22(8), 3843; https://doi.org/10.3390/ijms22083843 - 08 Apr 2021

Cited by 13 | Viewed by 5026

Abstract

Transactivation response DNA binding protein 43 kDa (TDP-43) is known to be a pathologic protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TDP-43 is normally a nuclear protein, but affected neurons of ALS or FTLD patients exhibit mislocalization of nuclear TDP-43 and cytoplasmic inclusions. Basic studies have suggested gain-of-neurotoxicity of aggregated TDP-43 or loss-of-function of intrinsic, nuclear TDP-43. It has also been hypothesized that the aggregated TDP-43 functions as a propagation seed of TDP-43 pathology. However, a mechanistic discrepancy between the TDP-43 pathology and neuronal dysfunctions remains. This article aims to review the observations of TDP-43 pathology in autopsied ALS and FTLD patients and address pathways of neuronal dysfunction related to the neuropathological findings, focusing on impaired clearance of TDP-43 and synaptic alterations in TDP-43-related ALS and FTLD. The former may be relevant to intraneuronal aggregation of TDP-43 and exocytosis of propagation seeds, whereas the latter may be related to neuronal dysfunction induced by TDP-43 pathology. Successful strategies of disease-modifying therapy might arise from further investigation of these subcellular alterations. Full article

(This article belongs to the Special Issue Understanding TDP-43-Mediated Mechanisms in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis)

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