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TDP-43 Biology and Pathology
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TDP-43 Biology and Pathology

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 (31 October 2023) | Viewed by 17835

Special Issue Editors

Prof. Dr. Junichi Kawada

E-Mail Website
Guest Editor
Department of Neurology, Fukuoka University, Fukuoka, Japan
Interests: neurodegenerative diseases; developmental neurobiology; cell biology
Dr. Yoshio Tsuboi

E-Mail Website
Guest Editor
Department of Neurology, Fukuoka University, Fukuoka, Japan
Interests: neurology; Perry disease; Parkinson’s disease

Special Issue Information

Dear Colleagues, 

Abnormal aggregates of TAR DNA-binding protein 43 kDa (TDP-43) are major hallmarks of several types of neurodegenerative disease, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FLTD), and Perry disease. Such diseases have been categorized as TDP-43 proteinopathies. Furthermore, TDP-43 aggregates have been detected in patients with Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. Although TDP-43 is essential for nucleic acid metabolism, cellular homeostasis, and embryonic development, it has been hypothesized that TDP-43 dysfunction and aggregation cause neurodegeneration. Recent evidence indicates that pathological TDP-43 aggregates in the cytoplasm of neurons exhibit amyloid-like filament structures. However, it remains unclear how these filaments are formed in the brain and spinal cord. In addition, there seem to be complicated loss-of-function and gain-of-toxicity mechanisms in the TDP-43 pathology. Thus, a further understanding of the biological functions of TDP-43 and its disease-triggering mechanisms has important medical implications toward developing novel potential therapeutic strategies to treat such devastating neurodegenerative diseases.

The aim of this Special Issue of the International Journal of Molecular Sciences is to attract high-quality papers covering the biological and pathological aspects of TDP-43. Contributors are encouraged to submit articles showing novel results, viewpoints, perspectives, and/or methodologies. The articles of this Special Issue will provide a cohesive picture of the state-of-the-art research in this field and help to advance our understanding of the broad spectrum of TDP-43 proteinopathies.

Prof. Dr. Junichi Kawada
Dr. Yoshio Tsuboi
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
  • RNA metabolism
  • aggregation
  • phase separation
  • neurodegenerative diseases
  • ALS
  • FTLD
  • Perry disease

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Published Papers (3 papers)

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Research

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16 pages, 21702 KiB  
Article
Nuclear Expression of TDP-43 Is Linked with Morphology and Ubiquitylation of Cytoplasmic Aggregates in Amyotrophic Lateral Sclerosis
by Hiroyuki Yabata, Yuichi Riku, Hiroaki Miyahara, Akio Akagi, Jun Sone, Makoto Urushitani, Mari Yoshida and Yasushi Iwasaki
Int. J. Mol. Sci. 2023, 24(15), 12176; https://doi.org/10.3390/ijms241512176 - 29 Jul 2023
Cited by 4 | Viewed by 4089
Abstract
The transactive response DNA-binding protein of 43 kDa (TDP-43) is a pathological protein of amyotrophic lateral sclerosis (ALS). TDP-43 pathology is characterized by a combination of the cytoplasmic aggregation and nuclear clearance of this protein. However, the mechanisms underlying TDP-43 pathology have not [...] Read more.
The transactive response DNA-binding protein of 43 kDa (TDP-43) is a pathological protein of amyotrophic lateral sclerosis (ALS). TDP-43 pathology is characterized by a combination of the cytoplasmic aggregation and nuclear clearance of this protein. However, the mechanisms underlying TDP-43 pathology have not been fully clarified. The aim of this study was to evaluate the relationships between the expression level of nuclear TDP-43 and the pathological properties of cytoplasmic aggregates in autopsied ALS cases. We included 22 consecutively autopsied cases with sporadic TDP-43-related ALS. The motor neuron systems were neuropathologically assessed. We identified 790 neurons with cytoplasmic TDP-43 inclusions from the lower motor neuron system of included cases. Nuclear TDP-43 disappeared in 84% (n = 660) and expressed in 16% (n = 130) of neurons with cytoplasmic inclusions; the former was defined as TDP-43 cytoplasmic immunoreactivity (c-ir), and the latter was defined as nuclear and cytoplasmic immunoreactivity (n/c-ir). Morphologically, diffuse cytoplasmic inclusions were significantly more prevalent in TDP-43 n/c-ir neurons than in c-ir neurons, while skein-like and round inclusions were less prevalent in n/c-ir neurons. The cytoplasmic inclusions of TDP-43 n/c-ir neurons were phosphorylated but poorly ubiquitylated when compared with those of c-ir neurons. TDP-43 n/c-ir neurons became less dominant than the c-ir neurons among cases with a prolonged disease duration. The expression level of nuclear TDP-43 was significantly lower in n/c-ir neurons than in normal neurons without cytoplasmic inclusions. Our results indicate that the maturation of cytoplasmic TDP-43 inclusions correlates with the depletion of nuclear TDP-43 in each affected neuron. This finding supports the view that an imbalance between nuclear and cytoplasmic TDP-43 may be an essential pathway to TDP-43 pathology. Full article
(This article belongs to the Special Issue TDP-43 Biology and Pathology)
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Review

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23 pages, 3360 KiB  
Review
TDP-43 Proteinopathy and Tauopathy: Do They Have Pathomechanistic Links?
by Yuichi Riku, Mari Yoshida, Yasushi Iwasaki, Gen Sobue, Masahisa Katsuno and Shinsuke Ishigaki
Int. J. Mol. Sci. 2022, 23(24), 15755; https://doi.org/10.3390/ijms232415755 - 12 Dec 2022
Cited by 20 | Viewed by 6171
Abstract
Transactivation response DNA binding protein 43 kDa (TDP-43) and tau are major pathological proteins of neurodegenerative disorders, of which neuronal and glial aggregates are pathological hallmarks. Interestingly, accumulating evidence from neuropathological studies has shown that comorbid TDP-43 pathology is observed in a subset [...] Read more.
Transactivation response DNA binding protein 43 kDa (TDP-43) and tau are major pathological proteins of neurodegenerative disorders, of which neuronal and glial aggregates are pathological hallmarks. Interestingly, accumulating evidence from neuropathological studies has shown that comorbid TDP-43 pathology is observed in a subset of patients with tauopathies, and vice versa. The concomitant pathology often spreads in a disease-specific manner and has morphological characteristics in each primary disorder. The findings from translational studies have suggested that comorbid TDP-43 or tau pathology has clinical impacts and that the comorbid pathology is not a bystander, but a part of the disease process. Shared genetic risk factors or molecular abnormalities between TDP-43 proteinopathies and tauopathies, and direct interactions between TDP-43 and tau aggregates, have been reported. Further investigations to clarify the pathogenetic factors that are shared by a broad spectrum of neurodegenerative disorders will establish key therapeutic targets. Full article
(This article belongs to the Special Issue TDP-43 Biology and Pathology)
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23 pages, 5742 KiB  
Review
Molecular Dissection of TDP-43 as a Leading Cause of ALS/FTLD
by Yoshitaka Tamaki and Makoto Urushitani
Int. J. Mol. Sci. 2022, 23(20), 12508; https://doi.org/10.3390/ijms232012508 - 19 Oct 2022
Cited by 32 | Viewed by 6848
Abstract
TAR DNA binding protein 43 (TDP-43) is a DNA/RNA binding protein involved in pivotal cellular functions, especially in RNA metabolism. Hyperphosphorylated and ubiquitinated TDP-43-positive neuronal cytoplasmic inclusions are identified in the brain and spinal cord in most cases of amyotrophic lateral sclerosis (ALS) [...] Read more.
TAR DNA binding protein 43 (TDP-43) is a DNA/RNA binding protein involved in pivotal cellular functions, especially in RNA metabolism. Hyperphosphorylated and ubiquitinated TDP-43-positive neuronal cytoplasmic inclusions are identified in the brain and spinal cord in most cases of amyotrophic lateral sclerosis (ALS) and a substantial proportion of frontotemporal lobar degeneration (FTLD) cases. TDP-43 dysfunctions and cytoplasmic aggregation seem to be the central pathogenicity in ALS and FTLD. Therefore, unraveling both the physiological and pathological mechanisms of TDP-43 may enable the exploration of novel therapeutic strategies. This review highlights the current understanding of TDP-43 biology and pathology, describing the cellular processes involved in the pathogeneses of ALS and FTLD, such as post-translational modifications, RNA metabolism, liquid–liquid phase separation, proteolysis, and the potential prion-like propagation propensity of the TDP-43 inclusions. Full article
(This article belongs to the Special Issue TDP-43 Biology and Pathology)
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