Related Experiment Video

Updated: Mar 16, 2026

Gait Analysis of Age-dependent Motor Impairments in Mice with Neurodegeneration
07:46

Gait Analysis of Age-dependent Motor Impairments in Mice with Neurodegeneration

Published on: June 18, 2018

12.7K

Atypical parkinsonism-associated retromer mutant alters endosomal sorting of specific cargo proteins

Kirsty J McMillan1, Matthew Gallon1, Adam P Jellett1

  • 1School of Biochemistry, University of Bristol, Bristol BS8 1TD, England, UK.

The Journal of Cell Biology
|August 17, 2016
PubMed

Insights

Retromer complex dysfunction, linked to neurodegenerative diseases, was studied using proteomics. A specific VPS26A mutation disrupts cargo sorting, revealing a new mechanism in atypical parkinsonism.

Area of Science:

  • Cell Biology
  • Neuroscience
  • Proteomics

Background:

  • The retromer complex is crucial for endosomal sorting of integral membrane proteins.
  • Retromer dysfunction is implicated in neurodegenerative diseases.
  • VPS26A mutations, including p.K93E, p.M112V, and p.K297X, are linked to atypical parkinsonism.

Purpose of the Study:

  • To comprehensively map the retromer interactome using quantitative proteomics.
  • To investigate how atypical parkinsonism-associated VPS26A mutations perturb the retromer interactome.
  • To elucidate the mechanism of altered endosomal sorting in VPS26A mutants.

Main Methods:

  • Quantitative proteomics was employed to analyze the retromer interactome.
  • A comparative proteomic methodology was established to study mutant interactomes.
  • Analysis focused on the interaction of VPS26A mutants with cargo adaptors like SNX27.

Main Results:

  • A detailed map of the retromer complex interactome was generated.
  • VPS26A mutants associated with atypical parkinsonism were shown to perturb this interactome.
  • A specific defect in the association between VPS26A (p.K297X) and the SNX27 adaptor was identified.
  • Altered endosomal sorting of PDZ ligand-containing cargo proteins was observed in a retromer mutant.

Conclusions:

  • Quantitative proteomics provides detailed insights into the retromer interactome.
  • VPS26A mutations disrupt retromer function, leading to altered endosomal cargo sorting.
  • This study reveals a novel mechanism contributing to atypical parkinsonism pathogenesis.

More Related Videos

Analysis of Endocytic Uptake and Retrograde Transport to the Trans-Golgi Network Using Functionalized Nanobodies in Cultured Cells11:05

Analysis of Endocytic Uptake and Retrograde Transport to the Trans-Golgi Network Using Functionalized Nanobodies in Cultured Cells

Published on: February 21, 2019

9.7K
Time-Lapse Video Microscopy for Assessment of EYFP-Parkin Aggregation as a Marker for Cellular Mitophagy09:29

Time-Lapse Video Microscopy for Assessment of EYFP-Parkin Aggregation as a Marker for Cellular Mitophagy

Published on: May 4, 2016

7.6K

Related Concept Videos

The Early Endosome: Endocytosis of Transferrin01:28

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...
5.1K
Export of Misfolded Proteins out of the ER01:32

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...
5.4K
Lysosomal Hydrolases01:22

Lysosomal Hydrolases

Lysosomes are the site for the degradation of macromolecules and biological polymers released during membrane trafficking events such as secretory, endocytic, autophagic, and phagocytic pathways. The membrane-enclosed area of the lysosome, called the lumen, contains hydrolytic enzymes active in an acidic environment. These acid hydrolases are functional at a pH between 4.5 and 5 and are involved in cellular processes such as cell signaling, energy metabolism, restoration of the plasma membrane,...
4.7K
Recycling Endosomes and Transcytosis00:58

Recycling Endosomes and Transcytosis

The recycling endosome, also known as the endosomal recycling compartment (ERC), is a part of the slow-recycling process of the endocytic pathway. Molecules internalized through receptor-mediated endocytosis are either degraded in the lysosomes or are recycled to the plasma membrane through the fast- or slow-recycling route.
The recycling endosome is not a single organelle but an extensively tubulated network of recycling pathways. It functions in storing molecules or transporting them across...
3.8K
ER Retrieval Pathway01:45

ER Retrieval Pathway

In the secretory pathway, vesicles transport proteins from one cellular compartment to another in forward transport to deliver the protein to its correct location. Occasionally, misfolded proteins and incorrect proteins escape their original compartments, and a retrieval pathway is used to return the escaped proteins to their original compartment.
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
5.0K
Rab Proteins01:14

Rab Proteins

Rab proteins constitute the largest family of monomeric GTPases, of which 70 members are present in humans. Rab proteins and their effectors regulate consecutive stages of vesicle transport such as vesicle transport, docking, and fusion to the correct recipient membrane.
Rab proteins switch between a cytosolic, GDP-bound inactive state and a membrane-anchored, GTP-bound active state. By themselves, Rabs show slow rates of GDP/GTP exchange and GTP hydrolysis. Thus, Rab proteins are considered...
5.4K