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Related Experiment Video

Updated: Mar 5, 2026

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

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ATP13A2/PARK9 regulates endo-/lysosomal cargo sorting and proteostasis through a novel PI(3, 5)P2-mediated

S Demirsoy¹, S Martin², S Motamedi¹

¹Laboratory for Cell Death Research and Therapy, Department of Cellular and Molecular Medicine, University of Leuven (KU Leuven).

Human Molecular Genetics

|March 24, 2017

Summary

ATP13A2 protein helps clear toxic proteins during cellular stress by facilitating cargo export via nanovesicles. Its scaffolding role, independent of its ATPase activity, is crucial for cellular proteostasis in Parkinson's disease models.

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

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

Published on: February 21, 2019

Area of Science:

Cell Biology
Neuroscience
Genetics

Background:

ATP13A2 (PARK9) is a lysosomal ATPase linked to Parkinson's disease (PD) and Kufor-Rakeb Syndrome (KRS).
Its function in stressed cells, particularly its N-terminal domain, remains poorly understood.
Understanding ATP13A2's role is vital for neurodegenerative disease research.

Purpose of the Study:

To investigate the physiological role of ATP13A2 in cells experiencing proteotoxic stress.
To elucidate the function of ATP13A2's N-terminal domain and its catalytic activity.
To determine ATP13A2's involvement in protein degradation pathways and vesicular trafficking.

Main Methods:

Generated cell lines overexpressing wild-type (WT), catalytically inactive (D508N), and N-terminal mutants of ATP13A2, alongside shRNA for ATP13A2 silencing.
Induced proteotoxic stress using Bortezomib (proteasome inhibitor).
Analyzed ubiquitin-conjugated protein accumulation, autophagic degradation, endocytic vesicle relocation, and nanovesicle cargo export.
Investigated the role of PI(3,5)P2 binding and PIKfyve in ATP13A2-mediated trafficking.

Main Results:

Overexpression of WT or mutant ATP13A2 reduced intracellular ubiquitin-protein accumulation under proteotoxic stress, independent of autophagy.
ATP13A2 silencing exacerbated ubiquitin-protein accumulation, mirroring KRS patient phenotypes.
ATP13A2 promoted endocytic vesicle relocation and enhanced cargo export via nanovesicles.
Impaired PI(3,5)P2 binding or PIKfyve inhibition disrupted trafficking and rescued protein accumulation.

Conclusions:

ATP13A2 plays a crucial, activity-independent scaffolding role in trafficking and exporting intracellular cargo during proteotoxic stress.
This function is vital for maintaining proteostasis and may be a therapeutic target for Parkinson's disease.
The PI(3,5)P2 pathway is integral to ATP13A2's stress-response mechanism.