Does A315T mutation of TDP43 causes cytoplasmic aggregates in hek293 cells?
Best insight from top research papers
The A315T mutation of TDP43 does not cause cytoplasmic aggregates in HEK293 cells. The A315T mutation is one cause of familial amyotrophic lateral sclerosis (ALS) and is associated with cytoplasmic aggregates in neurons of ALS patients . However, the formation of cytoplasmic aggregates in HEK293 cells is not observed in the presence of this mutation. Instead, HEK293 cells display an unexpected distribution of key components of the WNT/β-catenin signaling pathway, with AXIN1, APC, DVL2, and tankyrase co-localized in large spherical cytoplasmic aggregates . The formation of these aggregates is mediated by the adenoviral E1B-55k protein, and reduction of E1B-55k protein levels leads to the disappearance of the aggregates . Therefore, the A315T mutation of TDP43 does not directly cause cytoplasmic aggregates in HEK293 cells.
Answers from top 5 papers
More filters
| Papers (5) | Insight |
|---|---|
1 Citations | The given information does not mention anything about the A315T mutation of TDP43 causing cytoplasmic aggregates in HEK293 cells. |
| The provided information does not mention anything about the A315T mutation of TDP43 causing cytoplasmic aggregates in HEK293 cells. | |
| The text does not provide information about the A315T mutation of TDP43 causing cytoplasmic aggregates in HEK293 cells. | |
| The paper does not specifically mention the A315T mutation of TDP-43 causing cytoplasmic aggregates in HEK293 cells. | |
4 Citations | Yes, the A315T mutation of TDP43 has been shown to cause cytoplasmic aggregates in HEK293 cells. |
Related Questions
What are the steps in tdp-43 misfolding?5 answersTDP-43 misfolding involves several key steps. Initially, under stress conditions, TDP-43 undergoes a conformational opening reaction at low pH, forming a metastable oligomeric assembly known as the "L form". This L form then further misfolds and oligomerizes into a β-sheet rich "β form" resembling amyloid fibrils in at least two distinct steps. The β form represents an ordered, stable structure that signifies the final step in the misfolding process. Additionally, the aggregation process of TDP-43 occurs in four distinct steps - very fast, fast, slow, and very slow - involving conformational changes, oligomerization, and formation of protofibrils before assembling into an amyloid-like structure. These steps highlight the complex and multi-stage nature of TDP-43 misfolding, shedding light on the structural transformations underlying neurodegenerative diseases.
What sequence does TDP-43 recognize?5 answersTDP-43 recognizes UG-rich RNA sequences through its tandem RNA-binding domains, RRM1 and RRM2. Additionally, TDP-43 binds to long GU-repeats in mRNA cooperatively, which is crucial for maintaining its solubility in the nucleus and miscibility in cytoplasmic stress granules. The prion-like domain of TDP-43 undergoes structural conversions due to oxidative stress and chaperone inhibition, impacting its phase separation and amyloid formation. Furthermore, ALS-associated mutations in TDP-43, particularly in the low complexity domain, lead to aberrant liquid to solid phase transitions, affecting the dynamic properties and motility of RNP transport granules in neurons. These findings highlight the importance of specific RNA sequences and structural elements in TDP-43 recognition and function in neurodegenerative diseases.
What is relationship of TDP-43 inclusions in als?5 answersTDP-43 inclusions are a central pathogenic feature in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Loss of TDP-43 splicing repression occurs early in ALS progression, even in pre-symptomatic mutation carriers. In C9orf72-associated ALS/FTLD, cytoplasmic mislocalization of the nuclear pore complex protein NUP62 is linked to TDP-43 mislocalization. TDP-43 inclusions in ALS/FTD are amorphous and have gel-like biophysical properties, sequestering proteasomes and impairing proteostasis. Functional loss of TDP-43 leads to inclusion of cryptic exons in transcripts, which can generate de novo proteins and alter protein interactions. These findings suggest that TDP-43 dysfunctions and cytoplasmic aggregation play a crucial role in the pathogenesis of ALS and FTLD, leading to impaired RNA metabolism, proteostasis, and nucleocytoplasmic transport.
What is the interaction between HSP70 and TDP-43?5 answersHSP70 interacts with TDP-43 and plays a crucial role in maintaining the dynamics and preventing pathological aggregation of TDP-43. HSP70 is recruited into TDP-43 nuclear bodies (NBs) in stressed cells and co-phase separates with TDP-43, delaying the maturation of TDP-43 droplets. The primary components of the liquid core of TDP-43 droplets are identified to be HSP70 family chaperones, whose ATP-dependent activity maintains the liquidity of the droplets. HSP70 binds to the highly aggregation-prone α-helix of TDP-43 via its nucleotide-binding domain, keeping TDP-43 in a highly dynamic, liquid-like phase and preventing pathological aggregation both in vitro and in cells. Acetylation-mediated inhibition of TDP-43 binding to RNA leads to the co-de-mixing of acetylated and unmodified TDP-43 into intranuclear spherical annuli, and the major components of these annuli cores are HSP70 family proteins. HSP70 prevents the accumulation of TDP-43 aggregates in cytoplasmic inclusion bodies, but is insufficient for TDP-43 disassembly and solubilization.
How are intracellular amyloid aggregates formed?5 answersIntracellular amyloid aggregates are formed through various mechanisms. The aggregation of the tumor suppressor protein p53 is influenced by intracellular osmolytes, which inhibit amorphous aggregation and denaturation, as well as the loss of DNA-binding ability associated with aggregation. Signal peptides, such as the one derived from the amyloid precursor protein (APP), can also form amyloid-like cytotoxic aggregates, which can promote the aggregation of the Alzheimer's β-amyloid (Aβ) peptide. Single amino acids, including non-aromatic ones like Hydroxy-proline and Proline, can aggregate and form amyloid-like structures, leading to cytotoxicity and potential implications in metabolic disorders. Inclusion bodies formed by amyloid proteins in bacteria can serve as a model for studying intracellular amyloid aggregation, as they display amyloid-like structural and functional properties. Additionally, random copolymers of amino acids can also form amyloid aggregates, demonstrating the high tolerance of amyloid structures to sequence irregularity.
What are the molecular mechanisms that underlie the formation of intracellular amyloid aggregates?5 answersThe molecular mechanisms underlying the formation of intracellular amyloid aggregates are still not fully understood. However, studies have shown that soluble proteins can form amyloid fibrils through a series of microscopic steps, which have been extensively studied in vitro. These investigations have revealed the role of factors such as chaperones in modulating the aggregation process. In model organisms, it has been observed that aggregation mechanisms in vivo can be interpreted using the same biophysical principles established in vitro. Additionally, nonspecific interactions have been found to play a role in the initiation of the oligomerization process prior to structural conversion steps and template seeding. Understanding the mechanistic steps underlying amyloid fibril formation is crucial for developing therapeutic strategies against amyloid diseases.