scholarly journals Stress Granule Assembly Can Facilitate but Is Not Required for TDP-43 Cytoplasmic Aggregation

Biomolecules ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1367
Author(s):  
Nikita Fernandes ◽  
Luke Nero ◽  
Shawn M. Lyons ◽  
Pavel Ivanov ◽  
Telsa M. Mittelmeier ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Low Dose ◽  
Dna Binding Protein ◽  
Protein Abundance ◽  
Cytoplasmic Localization ◽  
P Bodies ◽  
Aggregation Behaviors ◽  
Protein Granules ◽  
Mutant Cells ◽  
Lateral Sclerosis

Stress granules (SGs) are hypothesized to facilitate TAR DNA-binding protein 43 (TDP-43) cytoplasmic mislocalization and aggregation, which may underly amyotrophic lateral sclerosis pathology. However, much data for this hypothesis is indirect. Additionally, whether P-bodies (PBs; related mRNA-protein granules) affect TDP-43 phenotypes is unclear. Here, we determine that induction of TDP-43 expression in yeast results in the accumulation of SG-like foci that in >90% of cases become the sites where TDP-43 cytoplasmic foci first appear. Later, TDP-43 foci associate less with SGs and more with PBs, though independent TDP-43 foci also accumulate. However, depleting or over-expressing yeast SG and PB proteins reveals no consistent trend between SG or PB assembly and TDP-43 foci formation, toxicity or protein abundance. In human cells, immunostaining endogenous TDP-43 with different TDP-43 antibodies reveals distinct localization and aggregation behaviors. Following acute arsenite stress, all phospho-TDP-43 foci colocalize with SGs. Interestingly, in SG assembly mutant cells (G3BP1/2ΔΔ), TDP-43 is enriched in nucleoli. Finally, formation of TDP-43 cytoplasmic foci following low-dose chronic arsenite stress is impaired, but not completely blocked, in G3BP1/2ΔΔ cells. Collectively, our data suggest that SG and PB assembly may facilitate TDP-43 cytoplasmic localization and aggregation but are likely not essential for these events.

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.

scholarly journals Methodology Aspects of Colony Maintain for a Murine Model of Amyotrophic Lateral Sclerosis (ALS) TDP-43 Proteinopathy

Animals ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 2329
Author(s):  
César Álvaro-Alonso ◽  
Águeda Ferrer-Donato ◽  
Elizabeth Fernández-Torres ◽  
Mónica Carballo-Villa ◽  
Carmen M. Fernandez-Martos
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Genetic Basis ◽  
Basic Research ◽  
Dna Binding Protein ◽  
Animal Experimentation ◽  
Genetically Engineered ◽  
Reproductive Parameters ◽  
Offspring Genotype ◽  
Pcr Assays ◽  
Lateral Sclerosis

The use of genetically engineered mouse (GEMs) models provides an unprecedented opportunity to study the genetic basis of diseases and gene function, therefore it is paramount to determine reproductive parameters that guarantee proper colony maintenance. We studied the reproductive parameters of mice hemizygous for TDP-43A315T transgene, which are viable, fertile, and express a mutant human TAR DNA binding protein (hTDP-43) cDNA harboring an amino acid substitution associated with familial amyotrophic lateral sclerosis (fALS). TDP43A315T mice were backcrossed to a C57Bl6/J pure background for four consecutive generations. The Tg offspring genotype were then confirmed by PCR assays. Our statistical analysis indicated there were no differences in the sex and number of pups per offspring when hemizygous female and male TDP43A315T mice were backcrossed to C57Bl6/J mice. Interestingly, our results showed significant differences in the number of offspring expressing the transgene when hemizygous TDP43A315T male mice were used as breeders. Therefore, our findings suggest that male TDP43A315T mice transfer the transgene with a greater genetic strengths. Such is an important breeding consideration to ensure the principle of reduction in animal experimentation considering most basic research with models focuses on males and excludes female mice.

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