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 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 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.

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 Nucleolin Rescues TDP-43 Toxicity in Yeast and Human Cell Models

2021 ◽  
Vol 15 ◽  
Author(s):  
Caterina Peggion ◽  
Maria Lina Massimino ◽  
Roberto Stella ◽  
Raissa Bortolotto ◽  
Jessica Agostini ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cell Viability ◽  
Human Cell ◽  
Neurodegenerative Disorders ◽  
Nuclear Protein ◽  
Human Cells ◽  
Cell Models ◽  
Nuclear Retention ◽  
Beneficial Effects ◽  
Lateral Sclerosis

TDP-43 is a nuclear protein involved in pivotal processes, extensively studied for its implication in neurodegenerative disorders. TDP-43 cytosolic inclusions are a common neuropathologic hallmark in amyotrophic lateral sclerosis (ALS) and related diseases, and it is now established that TDP-43 misfolding and aggregation play a key role in their etiopathology. TDP-43 neurotoxic mechanisms are not yet clarified, but the identification of proteins able to modulate TDP-43-mediated damage may be promising therapeutic targets for TDP-43 proteinopathies. Here we show by the use of refined yeast models that the nucleolar protein nucleolin (NCL) acts as a potent suppressor of TDP-43 toxicity, restoring cell viability. We provide evidence that NCL co-expression is able to alleviate TDP-43-induced damage also in human cells, further supporting its beneficial effects in a more consistent pathophysiological context. Presented data suggest that NCL could promote TDP-43 nuclear retention, reducing the formation of toxic cytosolic TDP-43 inclusions.

Exploring Aromatic Medicinal Compounds for the Treatment of Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 16 (10) ◽  
pp. 1934578X2110308
Author(s):  
Fahad Hassan Shah ◽  
Song Ja Kim
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Major Gene ◽  
Dna Binding Protein ◽  
Chemical Affinity ◽  
Drug Candidates ◽  
Medicinal Compounds ◽  
Candidate Drug ◽  
Lateral Sclerosis

Purpose: Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative condition, in which motor neurons start to degenerate due to the accumulation of protein aggregates in the neuron cytoplasm. The formation of aggregates causes neurotoxicity, facilitated by the N-terminal domain (NTD) of the transactive response DNA-binding protein-43 (TDP-43). Therapies used to treat ALS manage secondary symptoms, but do not stop the activity of the rogue NTD domain of TDP-43. Therefore, new drug candidates should be designed to deal efficiently with this disease by inhibiting the domains involved in the development of ALS. This study determined the chemical affinity of aromatic medicinal compounds with NTD. Screening of 1323 medicinal compounds was conducted with PYRX 0.9 software against NTD. Compounds obtained from this analysis were further used to predict absorption, distribution, metabolism, excretion, and toxic (ADMET) properties and their effect on major gene targets of ALS. Results: From 1300 + compounds, acetovanillone showed binding affinity for NTD and had good ADMET and drug likeness attributes. This compound reduced the expression of CXCL2, NOP56, and SOD1 genes implicated in ALS pathogenesis. Conclusion: These results concluded that acetovanillone is a candidate drug for in vitro and clinical studies into the exploitation of drugs within ALS therapeutics.

scholarly journals Neuropathology of Speech Network Distinguishes Bulbar From Nonbulbar Amyotrophic Lateral Sclerosis

2019 ◽  
Vol 79 (3) ◽  
pp. 284-295
Author(s):  
Sanjana Shellikeri ◽  
Julia Keith ◽  
Sandra E Black ◽  
Lorne Zinman ◽  
Yana Yunusova
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Dna Binding ◽  
Cognitive Deficits ◽  
Regional Distribution ◽  
Neuronal Loss ◽  
Dna Binding Protein ◽  
Motor Functions ◽  
Bulbar Symptoms ◽  
Bulbar Onset ◽  
Lateral Sclerosis

Abstract Bulbar amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative subtype affecting speech and swallowing motor functions as well as associated with the burden of cognitive deficits. The neuroanatomical underpinnings of bulbar ALS are not well understood. The aim of this study was to compare neuropathology of the speech network (SpN) between 3 cases of bulbar-onset ALS (bALS), 3 cases of spinal-onset ALS (sALS) with antemortem bulbar ALS (sALSwB) against 3 sALS without antemortem bulbar ALS (sALSnoB) and 3 controls. Regional distribution and severity of neuronal loss, TDP-43 (transactive response DNA-binding protein of 43 kDa), and tau proteinopathy were examined. All 3 bALS cases showed marked neuronal loss and severe proteinopathy across most SpN regions; sALSwB cases showed no neuronal loss but mild and variable TDP-43 pathology in focal regions; sALSnoB cases demonstrated an absence of pathology. Two bALS cases had coexisting tauopathy in SpN regions, which was not noted in any sALS cases. The findings suggested that bALS may have a distinct neuropathological signature characterized by marked neuronal loss and polypathology in the SpN. Milder TDP-43 pathology in the SpN for sALSwB cases suggested a link between severity of bulbar ALS and SpN damage. Findings support a clinicopathologic link between bulbar symptoms and pathology in the SpN.

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