Video Experimental Relacionado

Updated: Aug 26, 2025

Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles

Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles

Published on: October 18, 2024

Dos genes de FTD-ALS convergen en la vía endosómica para inducir la patología y la degeneración de TDP-43

Wei Shao¹, Tiffany W Todd¹, Yanwei Wu¹

¹Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.

Science (New York, N.Y.)

|October 6, 2022

Resumen

La demencia frontotemporal y la ELA implican los genes C9orf72 y TBK1. La agregación de C9orf72 afecta a la TBK1, empeorando la neurodegeneración y la patología de la TDP-43.

Área de la Ciencia:

La neurociencia
La genética
Biología molecular

Sus antecedentes:

La demencia frontotemporal y la esclerosis lateral amiotrófica (ALS-FT) están vinculadas a las expansiones del gen C9orf72 y a las mutaciones del gen TBK1.
Comprender los mecanismos moleculares que conectan estos factores genéticos es crucial para la patogénesis de FTD-ALS.

Objetivo del estudio:

Investigar la relación funcional entre la agregación de C9orf72 y la actividad de la quinasa TBK1 en la ELA-FT.
Para aclarar el papel de TBK1 en la neurodegeneración asociada con las expansiones repetidas de C9orf72.

Principales métodos:

Se estudió la fosforilación y el secuestro de TBK1 en respuesta a la agregación C9orf72 poli (Gly-Ala) [poli (GA) ] en modelos celulares y en ratones.
Se utilizó un modelo de ratón mutante TBK1-R228H para evaluar el impacto de la actividad reducida de TBK1 en los fenotipos inducidos por poli-GA.
Investigó el papel de la vía endosómica en la patología TDP-43.

Principales resultados:

La agregación de C9orf72 poly ((GA) conduce a la fosforilación de TBK1, al secuestro en inclusiones y a la pérdida de la actividad de la quinasa.
La actividad reducida de TBK1 en ratones exacerbó la patología y la disfunción endosómica TDP-43 inducida por poli (GA).
La inhibición de la vía endosómica promovió la agregación de TDP-43, subrayando su importancia.

Conclusiones:

Se identifica una vía que une C9orf72, TBK1 y TDP-43, conectando aspectos clave de FTD-ALS.
La disfunción de TBK1 y el deterioro de la vía endosómica son factores críticos que contribuyen a la neurodegeneración mediada por C9orf72.
Este estudio proporciona un marco molecular unificado para comprender la patogénesis de FTD-ALS.

Más Videos Relacionados

Optogenetic Phase Transition of TDP-43 in Spinal Motor Neurons of Zebrafish Larvae

Optogenetic Phase Transition of TDP-43 in Spinal Motor Neurons of Zebrafish Larvae

Published on: February 25, 2022

Novel Atomic Force Microscopy Based Biopanning for Isolation of Morphology Specific Reagents against TDP-43 Variants in Amyotrophic Lateral Sclerosis

Novel Atomic Force Microscopy Based Biopanning for Isolation of Morphology Specific Reagents against TDP-43 Variants in Amyotrophic Lateral Sclerosis

Published on: February 12, 2015

Videos de Conceptos Relacionados

Export of Misfolded Proteins out of the ER

Export of Misfolded Proteins out of the ER

After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...

Amyloid Fibrils

Amyloid Fibrils

Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...

Tail-anchoring of Proteins in the ER Membrane

Tail-anchoring of Proteins in the ER Membrane

Tail-anchored, or TA, proteins are estimated to make up to 3-5% of membrane proteins found in the eukaryotic cell. Such proteins have a single transmembrane domain located approximately 30 amino acid residues upstream from the C-terminal end. As a result, the signal recognition particle (SRP) cannot guide a TA protein to the ER membrane for cotranslational insertion. Hence, they are integrated into the ER membrane post-translationally using their C-terminal end as the anchor. TA proteins...

Enzyme-linked Receptors

Enzyme-linked Receptors

Enzyme-linked receptors are proteins that act as both receptor and enzyme, activating multiple intracellular signals. This is a large group of receptors that include the receptor tyrosine kinase (RTK) family. Many growth factors and hormones bind to and activate the RTKs.
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...

The Early Endosome: Endocytosis of Transferrin

The Early Endosome: Endocytosis of Transferrin

Essential proteins such as insulin or low-density lipoprotein (LDL) and micronutrients such as iron enter a eukaryotic cell through receptor-mediated endocytosis. Subsequently, the early endosomes fuse with the vesicles containing such receptor-ligand complexes and play a vital role in sorting the incoming ligands and receptors. While the ligands are either degraded inside the vesicle or released into the cytosol, their receptors are returned to the plasma membrane for further rounds of...