TDP-43 Proteinopathies

Diseases characterized by the presence of abnormally phosphorylated, ubiquitinated, and cleaved DNA-binding protein TDP-43 in affected brain and spinal cord. Inclusions of the pathologic protein in neurons and glia, without the presence of AMYLOID, is the major feature of these conditions, thus making these proteinopathies distinct from most other neurogenerative disorders in which protein misfolding leads to brain amyloidosis. Both frontotemporal lobar degeneration and AMYOTROPHIC LATERAL SCLEROSIS exhibit this common method of pathogenesis and thus they may represent two extremes of a continuous clinicopathological spectrum of one disease.

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Networked: 129 relevant articles (3 outcomes, 13 trials/studies)

Relationship Network

Disease Context: Research Results

Related Diseases

1.	Frontotemporal Lobar Degeneration (Semantic Dementia)
2.	Neurodegenerative Diseases (Neurodegenerative Disease)
3.	Tauopathies
4.	Cystic Fibrosis (Mucoviscidosis)
5.	Amyotrophic Lateral Sclerosis (Lou Gehrig's Disease)

Experts

1.	Trojanowski, John Q: 20 articles (12/2015 - 07/2007)
2.	Hasegawa, Masato: 16 articles (11/2014 - 11/2008)
3.	Lee, Virginia M-Y: 15 articles (12/2015 - 07/2007)
4.	Arai, Tetsuaki: 13 articles (12/2014 - 11/2008)
5.	Nonaka, Takashi: 11 articles (05/2014 - 11/2008)
6.	Akiyama, Haruhiko: 11 articles (05/2014 - 11/2008)
7.	Kwong, Linda K: 9 articles (12/2015 - 07/2007)
8.	Neumann, Manuela: 7 articles (06/2010 - 07/2007)
9.	Xu, Yan: 6 articles (12/2015 - 07/2007)
10.	Shaw, Christopher E: 6 articles (04/2015 - 01/2008)

Drugs and Biologics

Drugs and Important Biological Agents (IBA) related to TDP-43 Proteinopathies:

1.	protein TDP-43 (TDP-43)IBA 07/01/2011 - "Our work also suggests that decreasing the abundance of neurotoxic TDP-43 species, enhancing degradation or clearance of such TDP-43 derivatives and blocking the spread of the disease phenotype may have therapeutic potential for TDP-43 proteinopathies." 02/16/2010 - "Our study indicates that simply increasing hTDP-43 expression is sufficient to cause neurotoxicity in vivo, suggesting that aberrant regulation of TDP-43 expression or decreased clearance of hTDP-43 may contribute to the pathogenesis of TDP-43 proteinopathy." 08/10/2012 - "This study not only establishes an important role of TDP-43 in the long term survival and functioning of the mammalian spinal cord motor neurons, but also establishes that loss of TDP-43 function could be one major cause for neurodegeneration in ALS with TDP-43 proteinopathies." 04/10/2012 - "Identification of mutations in the gene encoding TDP-43 (TARDBP) in familial ALS confirms a mechanistic link between misaccumulation of TDP-43 and neurodegeneration and provides an opportunity to study TDP-43 proteinopathies in human neurons generated from patient fibroblasts by using induced pluripotent stem cells (iPSCs). " 01/01/2012 - "These studies represent the first in vivo demonstration of a pathological role for TDP-25 and strongly suggest that the onset of cognitive deficits in TDP-43 proteinopathies is independent of TDP-43 inclusions. "
2.	dimebolin (dimebon)IBA 07/21/2009 - "The results indicate that MB and dimebon may be useful for the treatment of ALS, FTLD-U and other TDP-43 proteinopathies."
3.	AntibodiesIBA 01/01/2015 - "These antibodies can be used in future studies of TDP-43 proteinopathies. " 01/06/2012 - "The antibodies and methods used in this study will be useful for the characterization of abnormal TDP-43 in human materials, as well as in vitro and animal models for TDP-43 proteinopathies."
4.	UbiquitinIBA 04/01/2015 - "We review the progressive development of TDP-43 proteinopathy from cytoplasmic mislocalization and misfolding through to macroaggregation and the addition of phosphate and ubiquitin moieties. " 08/10/2012 - "Importantly, the majority of the ALS cases are with TDP-43 proteinopathies characterized with TDP-43-positive, ubiquitin-positive inclusions (UBIs) in the cytosol. " 09/01/2008 - "Histologic examination of the 2 autopsy cases was consistent with a pathologic diagnosis of TDP-43 proteinopathy; specifically frontotemporal lobar degeneration with ubiquitin-only immunoreactive changes, type 1. There were significant differences between these 6 patients and the 2 groups of autopsy confirmed FTD and Lewy body disease patients. " 12/01/2011 - "The vast majority of NCIs in the brain and spinal cord also label for ubiquitin and p62, however, we have previously reported a subset of TDP-43 proteinopathy patients who have unusual and abundant p62 positive, TDP-43 negative inclusions in the cerebellum and hippocampus. " 01/01/2010 - "We report that expression of this fragment within cells leads to a time-dependent formation of inclusions that are immunoreactive for both ubiquitin and phosphorylated TDP-43, thus recapitulating pathological hallmarks of TDP-43 proteinopathies. "
5.	Proteasome Endopeptidase Complex (Proteasome)IBA 04/01/2015 - "Drawing from cellular and animal studies, we explore the feasibility of therapeutics that act at each point in pathogenesis, from mitigating genetic risk using antisense oligonucleotides to modulating TDP-43 proteinopathy itself using small molecule activators of autophagy, the ubiquitin-proteasome system, or the chaperone network. " 12/01/2014 - "Our results suggest that higher turnover of disease-associated mutant TDP-43 proteins through the ubiquitin proteasome system is pathogenetically relevant and highlight the significance of proteolysis in the pathogenetic mechanism of TDP-43 proteinopathy. "
6.	Insulin Receptor Substrate ProteinsIBA 11/01/2014 - "This study investigated the expression of abnormal serine phosphorylation of insulin receptor substrate 1 (IRS1) in 157 human brain autopsy cases that included AD, tauopathies, α-synucleinopathies, TDP-43 proteinopathies, and normal aging. "
7.	Antisense OligonucleotidesIBA 04/01/2015 - "Drawing from cellular and animal studies, we explore the feasibility of therapeutics that act at each point in pathogenesis, from mitigating genetic risk using antisense oligonucleotides to modulating TDP-43 proteinopathy itself using small molecule activators of autophagy, the ubiquitin-proteasome system, or the chaperone network. "
8.	Serine (L-Serine)FDA Link 11/01/2014 - "This study investigated the expression of abnormal serine phosphorylation of insulin receptor substrate 1 (IRS1) in 157 human brain autopsy cases that included AD, tauopathies, α-synucleinopathies, TDP-43 proteinopathies, and normal aging. "
9.	Messenger RNA (mRNA)IBA 10/01/2014 - "Affymetrix exon arrays were used to study mRNA expression and splicing in lower motor neurones obtained by laser capture microdissection of autopsy tissue from individuals with sporadic ALS and TDP-43 proteinopathy. "
10.	Nucleic AcidsIBA 04/01/2009 - "These studies thus characterize the recognition between TDP-43 and nucleic acids and the mode of RRM2 self association, and provide molecular models for understanding the role of TDP-43 in cystic fibrosis and the neurodegenerative diseases related to TDP-43 proteinopathy."

Therapies and Procedures

1.	Therapeutics 04/01/2010 - "Understanding the mechanism of phosphorylation and truncation of TDP-43 and aggregate formation may be crucial for clarifying the pathogenesis of TDP-43 proteinopathy and for developing useful therapeutics." 04/01/2015 - "Drawing from cellular and animal studies, we explore the feasibility of therapeutics that act at each point in pathogenesis, from mitigating genetic risk using antisense oligonucleotides to modulating TDP-43 proteinopathy itself using small molecule activators of autophagy, the ubiquitin-proteasome system, or the chaperone network. "
2.	Lasers (Laser) 10/01/2014 - "Affymetrix exon arrays were used to study mRNA expression and splicing in lower motor neurones obtained by laser capture microdissection of autopsy tissue from individuals with sporadic ALS and TDP-43 proteinopathy. "