VPS35 Downregulation Alters Degradation Pathways in Neuronal Cells

Background: The vacuolar protein sorting 35 (VPS35) is the main component of the retromer recognition core complex system which regulates intracellular cargo protein sorting and trafficking. Downregulation of VPS35 has been linked to the pathogenesis of neurodegenerative disorders such Alzheimer’s a...

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Bibliographic Details
Published in:Journal of Alzheimer's disease 2021-01, Vol.84 (3), p.1079-1089
Main Authors: Filippone, Alessia, Li, Jian-Guo, Praticò, Domenico
Format: Article
Language:English
Subjects:
Alzheimer Disease - genetics
Alzheimer Disease - metabolism
Alzheimer's disease
Autophagy
Cargo
Cells, Cultured
Complex systems
Degradation
Down-Regulation
Endosomes
Endosomes - metabolism
Humans
Intracellular
Neurodegenerative diseases
Neurons - metabolism
Pathogenesis
Phagocytosis
Protein transport
Protein Transport - physiology
Proteins
Recognition
siRNA
Vesicular Transport Proteins - genetics
Vesicular Transport Proteins - metabolism
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Summary:Background: The vacuolar protein sorting 35 (VPS35) is the main component of the retromer recognition core complex system which regulates intracellular cargo protein sorting and trafficking. Downregulation of VPS35 has been linked to the pathogenesis of neurodegenerative disorders such Alzheimer’s and Parkinson’s diseases via endosome dysregulation. Objective: Here we show that the genetic manipulation of VPS35 affects intracellular degradation pathways. Methods: A neuronal cell line expressing human APP Swedish mutant was used. VPS35 silencing was performed treating cells with VPS35 siRNA or Ctr siRNA for 72 h. Results: Downregulation of VPS35 was associated with alteration of autophagy flux and intracellular accumulation of acidic and ubiquitinated aggregates suggesting that dysfunction of the retromer recognition core leads to a significant alteration in both pathways. Conclusion: Taken together, our data demonstrate that besides cargo sorting and trafficking, VPS35 by supporting the integral function of the retromer complex system plays an important role also as a critical regulator of intracellular degradation pathways.
ISSN:1387-2877
1875-8908
DOI:10.3233/JAD-210701