scholarly journals The Dying Forward Hypothesis of ALS: Tracing Its History

2021 ◽  
Vol 11 (3) ◽  
pp. 300
Author(s):  
Andrew Eisen
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Dementia ◽  
Nuclear Protein ◽  
Dna Binding Protein ◽  
System A ◽  
Cortical Involvement ◽  
Forward Process ◽  
Betz Cells ◽  
Lateral Sclerosis

The site of origin of amyotrophic lateral sclerosis (ALS), although unsettled, is increasingly recognized as being cortico-fugal, which is a dying-forward process primarily starting in the corticomotoneuronal system. A variety of iterations of this concept date back to over 150 years. Recently, the hallmark TAR DNA-binding protein 43 (TDP-43) pathology, seen in >95% of patients with ALS, has been shown to be largely restricted to corticofugal projecting neurons (“dying forward”). Possibly, soluble but toxic cytoplasmic TDP-43 could enter the axoplasm of Betz cells, subsequently causing dysregulation of nuclear protein in the lower brainstem and spinal cord anterior horn cells. As the disease progresses, cortical involvement in ALS becomes widespread, including or starting with frontotemporal dementia, implying a broader view of ALS as a brain disease. The onset at the motor and premotor cortices should be considered a nidus at the edge of multiple cortical networks which eventually become disrupted, causing failure of a widespread cortical connectome.

Cerebrospinal Fluid TAR DNA-Binding Protein 43 Combined with Tau Proteins as a Candidate Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Spectrum Disorders

2017 ◽  
Vol 44 (3-4) ◽  
pp. 144-152 ◽  
Author(s):  
Mara Bourbouli ◽  
Michael Rentzos ◽  
Anastasia Bougea ◽  
Vasiliki Zouvelou ◽  
Vasilios C. Constantinides ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cerebrospinal Fluid ◽  
Dna Binding ◽  
Frontotemporal Dementia ◽  
Tau Protein ◽  
Binding Protein ◽  
Dna Binding Protein ◽  
Amyloid Peptide ◽  
Spectrum Disorders ◽  
Lateral Sclerosis

Background: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are nowadays recognized as spectrum disorders with a molecular link, the TAR DNA-binding protein 43 (TDP-43), rendering it a surrogate biomarker for these disorders. Methods: We measured cerebrospinal fluid (CSF) levels of TDP-43, beta-amyloid peptide with 42 amino acids (Aβ42), total tau protein (τT), and tau protein phosphorylated at threonine 181 (τP-181) in 32 patients with ALS, 51 patients with FTD, and 17 healthy controls. Double-sandwich commercial enzyme-linked immunosorbent assays were used for measurements. Results: Both ALS and FTD patients presented with higher TDP-43 and τT levels compared to the control group. The combination of biomarkers in the form of the TDP-43 × τT / τP-181 formula achieved the best discrimination between ALS or FTD and controls, with sensitivities and specificities >0.8. Conclusion: Combined analysis of TDP-43, τT, and τP-181 in CSF may be useful for the antemortem diagnosis of ALS and FTD.

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

2021 ◽  
Vol 22 (8) ◽  
pp. 3843
Author(s):  
Yuichi Riku ◽  
Danielle Seilhean ◽  
Charles Duyckaerts ◽  
Susana Boluda ◽  
Yohei Iguchi ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Lobar Degeneration ◽  
Nuclear Protein ◽  
Dna Binding Protein ◽  
Neuronal Dysfunction ◽  
Loss Of Function ◽  
Cytoplasmic Inclusions ◽  
Disease Modifying Therapy ◽  
Basic Studies ◽  
Lateral Sclerosis

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.

scholarly journals Importance of the Q/N-rich Segment for Protein Stability and Activity of Endogenous Mouse TDP-43

2021 ◽  
Author(s):  
Toshiya Sato ◽  
Kanako Oda ◽  
Seiko Sakai ◽  
Rika Kato ◽  
Saori Yamamori ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Subcellular Localization ◽  
Protein Stability ◽  
Genome Editing ◽  
Nuclear Protein ◽  
Dna Binding Protein ◽  
Mouse Development ◽  
The Stability ◽  
Lateral Sclerosis ◽  
Mouse Lines

Abstract TAR DNA-binding protein 43 kDa (TDP-43), a nuclear protein, plays an important role in the molecular pathogenesis of amyotrophic lateral sclerosis (ALS). TDP-43 aggregation and translocation out of the nucleus are crucial factors in ALS. TDP-43 aggregation results from its resistance to degradation, to which the long-disordered C-terminal region (CTR) is thought to contribute. The CTR has two Gly, aromatic, and Ser-rich (GaroS) segments and an amyloidogenic core divided into a hydrophobic patch and a Gln/Asn (Q/N)-rich segment. Although TDP-43 lacking the CTR is known to be unstable, as observed in knock-in mice, it is unclear which of these segments contributes to the stability of TDP-43. Here, we generated 12 mouse lines lacking the various sub-regions of CTR by genome editing and compared the protein stability, activity, and subcellular localization of TDP-43. We demonstrated the functional diversity of the four segments of CTR, finding that the presence of Q/N-rich segment greatly restored the protein stability and activity of TDP-43. In addition, we found that the second GaroS deletion did not affect protein stability and mouse development.

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

2021 ◽  
Vol 22 (15) ◽  
pp. 7781
Author(s):  
Fiona Bright ◽  
Gabriella Chan ◽  
Annika van Hummel ◽  
Lars M. Ittner ◽  
Yazi D. Ke
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Dementia ◽  
Active Role ◽  
Dna Binding Protein ◽  
Ubiquitinated Protein ◽  
Immune Mediated ◽  
The Central Nervous System ◽  
Specific Association ◽  
Lateral Sclerosis

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.

scholarly journals Neuroanatomical Quantitative Proteomics Reveals Common Pathogenic Biological Routes between Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD)

2018 ◽  
Vol 20 (1) ◽  
pp. 4 ◽  
Author(s):  
Marina Iridoy ◽  
Irene Zubiri ◽  
María Zelaya ◽  
Leyre Martinez ◽  
Karina Ausín ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Dementia ◽  
Quantitative Proteomics ◽  
Binding Protein ◽  
Proteomics Analysis ◽  
Differential Proteins ◽  
Liquid Chromatography Tandem Mass ◽  
Specific Proteins ◽  
Lateral Sclerosis

(1) Background: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders with an overlap in clinical presentation and neuropathology. Common and differential mechanisms leading to protein expression changes and neurodegeneration in ALS and FTD were studied trough a deep neuroproteome mapping of the spinal cord. (2) Methods: A liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis of the spinal cord from ALS-TAR DNA-binding protein 43 (TDP-43) subjects, ubiquitin-positive frontotemporal lobar degeneration (FTLD-U) subjects and controls without neurodegenerative disease was performed. (3) Results: 281 differentially expressed proteins were detected among ALS versus controls, while 52 proteins were dysregulated among FTLD-U versus controls. Thirty-three differential proteins were shared between both syndromes. The resulting data was subjected to network-driven proteomics analysis, revealing mitochondrial dysfunction and metabolic impairment, both for ALS and FTLD-U that could be validated through the confirmation of expression levels changes of the Prohibitin (PHB) complex. (4) Conclusions: ALS-TDP-43 and FTLD-U share molecular and functional alterations, although part of the proteostatic impairment is region- and disease-specific. We have confirmed the involvement of specific proteins previously associated with ALS (Galectin 2 (LGALS3), Transthyretin (TTR), Protein S100-A6 (S100A6), and Protein S100-A11 (S100A11)) and have shown the involvement of proteins not previously described in the ALS context (Methanethiol oxidase (SELENBP1), Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN-1), Calcyclin-binding protein (CACYBP) and Rho-associated protein kinase 2 (ROCK2)).

scholarly journals Insight into the Folding and Dimerization Mechanisms of the N-Terminal Domain from Human TDP-43

2020 ◽  
Vol 21 (17) ◽  
pp. 6259
Author(s):  
Mirella Vivoli-Vega ◽  
Prandvera Guri ◽  
Fabrizio Chiti ◽  
Francesco Bemporad
Keyword(s):  
Molecular Weight ◽  
Amyotrophic Lateral Sclerosis ◽  
Nuclear Protein ◽  
Dna Binding Protein ◽  
Folding Kinetics ◽  
Terminal Domain ◽  
Insight Into ◽  
Lateral Sclerosis ◽  
Full Consensus

TAR DNA-binding protein 43 (TDP-43) is a 414-residue long nuclear protein whose deposition into intraneuronal insoluble inclusions has been associated with the onset of amyotrophic lateral sclerosis (ALS) and other diseases. This protein is physiologically a homodimer, and dimerization occurs through the N-terminal domain (NTD), with a mechanism on which a full consensus has not yet been reached. Furthermore, it has been proposed that this domain is able to affect the formation of higher molecular weight assemblies. Here, we purified this domain and carried out an unprecedented characterization of its folding/dimerization processes in solution. Exploiting a battery of biophysical approaches, ranging from FRET to folding kinetics, we identified a head-to-tail arrangement of the monomers within the dimer. We found that folding of NTD proceeds through the formation of a number of conformational states and two parallel pathways, while a subset of molecules refold slower, due to proline isomerism. The folded state appears to be inherently prone to form high molecular weight assemblies. Taken together, our results indicate that NTD is inherently plastic and prone to populate different conformations and dimeric/multimeric states, a structural feature that may enable this domain to control the assembly state of TDP-43.

scholarly journals Rapid in vitro quantification of TDP-43 and FUS mislocalisation for screening of gene variants implicated in frontotemporal dementia and amyotrophic lateral sclerosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lisa J. Oyston ◽  
Stephanie Ubiparipovic ◽  
Lauren Fitzpatrick ◽  
Marianne Hallupp ◽  
Lauren M. Boccanfuso ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Dementia ◽  
Nuclear Protein ◽  
Gene Mutations ◽  
Pharmacological Intervention ◽  
In Vitro Technique ◽  
Apoptosis Inducer ◽  
Lateral Sclerosis ◽  
Fus Protein

AbstractIdentified genetic mutations cause 20% of frontotemporal dementia (FTD) and 5-10% of amyotrophic lateral sclerosis (ALS) cases: however, for the remainder of patients the origin of disease is uncertain. The overlap in genetic, clinical and pathological presentation of FTD and ALS suggests these two diseases are related. Post-mortem, ~ 95% of ALS and ~ 50% of FTD patients show redistribution of the nuclear protein TDP-43 to the cytoplasm within affected neurons, while ~ 5% ALS and ~ 10% FTD show mislocalisation of FUS protein. We exploited these neuropathological features to develop an unbiased method for the in vitro quantification of cytoplasmic TDP-43 and FUS. Utilising fluorescently-tagged cDNA constructs and immunocytochemistry, the fluorescence intensity of TDP-43 or FUS was measured in the nucleus and cytoplasm of cells, using the freely available software CellProfiler. Significant increases in the amount of cytoplasmic TDP-43 and FUS were detectable in cells expressing known FTD/ALS-causative TARDBP and FUS gene mutations. Pharmacological intervention with the apoptosis inducer staurosporine and mutation in a secondary gene (CYLD) also induced measurable cytoplasmic mislocalisation of endogenous FUS and TDP-43, respectively. These findings validate this methodology as a novel in vitro technique for the quantification of TDP-43 or FUS mislocalisation that can be used for initial prioritisation of predicted FTD/ALS-causative mutations.

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