The role of mutant TAR DNA-binding protein 43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration

2011 ◽  
Vol 39 (4) ◽  
pp. 954-959 ◽  
Author(s):  
Jonathan Janssens ◽  
Gernot Kleinberger ◽  
Hans Wils ◽  
Christine Van Broeckhoven
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Dna Binding ◽  
Frontotemporal Lobar Degeneration ◽  
Binding Protein ◽  
Dna Binding Protein ◽  
Current Status ◽  
Disease Spectrum ◽  
Pathological Disease ◽  
Lateral Sclerosis

TDP-43 (TAR DNA-binding protein 43) has been identified as a key protein of ubiquitinated inclusions in brains of patients with ALS (amyotrophic lateral sclerosis) or FTLD (frontotemporal lobar degeneration), defining a new pathological disease spectrum. Recently, coding mutations have been identified in the TDP-43 gene (TARDBP), which further confirmed the pathogenic nature of the protein. Today, several animal models have been generated to gain more insight into the disease-causing pathways of the FTLD/ALS spectrum. This mini-review summarizes the current status of TDP-43 models, with a focus on mutant TDP-43.

scholarly journals Contribution of RNA/DNA Binding Protein Dysfunction in Oligodendrocytes in the Pathogenesis of the Amyotrophic Lateral Sclerosis/Frontotemporal Lobar Degeneration Spectrum Diseases

2021 ◽  
Vol 15 ◽  
Author(s):  
Chiara F. Valori ◽  
Manuela Neumann
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Dna Binding ◽  
Frontotemporal Lobar Degeneration ◽  
Binding Protein ◽  
Dna Binding Protein ◽  
Current Data ◽  
Fused In Sarcoma ◽  
Disease Spectrum ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two incurable neurodegenerative disorders, often considered as the extreme manifestations of a disease spectrum, as they share similar pathomechanisms. In support of this, pathological aggregation of the RNA/DNA binding proteins trans-activation response element DNA-binding protein 43 (TDP-43) or fused in sarcoma (FUS) is the pathological hallmark found in neurons and glial cells of subsets of patients affected by either condition (i.e., ALS/FTLD—TDP-43 or ALS/FTLD—FUS, respectively). Among glia, oligodendrocytes are the most abundant population, designated to ensheath the axons with myelin and to provide them with metabolic and trophic support. In this minireview, we recapitulate the neuropathological evidence for oligodendroglia impairment in ALS/FTLD. We then debate how TDP-43 and FUS target oligodendrocyte transcripts, thereby controlling their homeostatic abilities toward the axons. Finally, we discuss cellular and animal models aimed at investigating the functional consequences of manipulating TDP-43 and FUS in oligodendrocytes in vivo. Taken together, current data provide increasing evidence for an important role of TDP-43 and FUS-mediated oligodendroglia dysfunction in the pathogenesis of ALS/FTLD. Thus, targeting disrupted oligodendroglial functions may represent a new treatment approach for these conditions.

scholarly journals TDP-43 real-time quaking induced conversion reaction optimization and detection of seeding activity in CSF of amyotrophic lateral sclerosis and frontotemporal dementia patients

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Carlo Scialò ◽  
Thanh Hoa Tran ◽  
Giulia Salzano ◽  
Giovanni Novi ◽  
Claudia Caponnetto ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cerebrospinal Fluid ◽  
Dna Binding ◽  
Real Time ◽  
Frontotemporal Lobar Degeneration ◽  
Binding Protein ◽  
Dna Binding Protein ◽  
Conversion Reaction ◽  
The Real ◽  
Lateral Sclerosis

Abstract The pathological deposition of the transactive response DNA-binding protein of 43 kDa occurs in the majority (∼97%) of amyotrophic lateral sclerosis and in around 45% of frontotemporal lobar degeneration cases. Amyotrophic lateral sclerosis and frontotemporal lobar degeneration clinically overlap, presenting a continuum of phenotypes. Both amyotrophic lateral sclerosis and frontotemporal lobar degeneration lack treatments capable of interfering with the underlying pathological process and early detection of transactive response DNA-binding protein of 43 kDa pathology would facilitate the development of disease-modifying drugs. The real-time quaking-induced conversion reaction showed the ability to detect prions in several peripheral tissues of patients with different forms of prion and prion-like diseases. Despite transactive response DNA-binding protein of 43 kDa displays prion-like properties, to date the real-time quaking-induced conversion reaction technology has not yet been adapted to this protein. The aim of this study was to adapt the real-time quaking-induced conversion reaction technique for the transactive response DNA-binding protein of 43 kDa substrate and to exploit the intrinsic ability of this technology to amplify minute amount of mis-folded proteins for the detection of pathological transactive response DNA-binding protein of 43 kDa species in the cerebrospinal fluid of amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients. We first optimized the technique with synthetic transactive response DNA-binding protein of 43 kDa–pre-formed aggregates and with autopsy-verified brain homogenate samples and subsequently analysed CSF samples from amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients and controls. Transactive response DNA-binding protein of 43 kDa real-time quaking-induced conversion reaction was able to detect as little as 15 pg of transactive response DNA-binding protein of 43 kDa aggregates, discriminating between a cohort of patients affected by amyotrophic lateral sclerosis and frontotemporal lobar degeneration and age-matched controls with a total sensitivity of 94% and a specificity of 85%. Our data give a proof-of-concept that transactive response DNA-binding protein of 43 kDa is a suitable substrate for the real-time quaking-induced conversion reaction. Transactive response DNA-binding protein of 43 kDa real-time quaking-induced conversion reaction could be an innovative and useful tool for diagnosis and drug development in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. The cerebrospinal fluid detection of transactive response DNA-binding protein of 43 kDa pathological aggregates may be exploited as a disease biomarker for amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients.

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