English
 
Help Privacy Policy Disclaimer
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  Amyloid-like aggregating proteins cause lysosomal defects in neurons via gain-of-function toxicity

Riera-Tur, I., Schäfer, T., Hornburg, D., Mishra, A., Padilha, M. D., Fernandez-Mosquera, L., et al. (2021). Amyloid-like aggregating proteins cause lysosomal defects in neurons via gain-of-function toxicity. Life science alliance, 5(3): e202101185. doi:10.26508/lsa.202101185.

Item is

Basic

show hide
Genre: Journal Article
Alternative Title : Amyloid-like aggregating proteins cause lysosomal defects in neurons via gain-of-function toxicity

Files

show Files

Locators

show

Creators

show
hide
 Creators:
Riera-Tur, I., Author
Schäfer, Tillmann1, Author           
Hornburg, D.2, Author           
Mishra, Arhana, Author
Padilha, M. D., Author
Fernandez-Mosquera, L., Author
Feigenbutz, D., Author
Auer, P., Author
Mann, M.2, Author           
Baumeister, W.1, Author           
Klein, Rüdiger, Author
Meissner, Felix3, Author           
Raimundo, N., Author
Fernandez-Busnadiego, R.1, Author           
Dudanova, I., Author
Affiliations:
1Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565142              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              
3Meissner, Felix / Experimental Systems Immunology, Max Planck Institute of Biochemistry, Max Planck Society, ou_2149678              

Content

show
hide
Free keywords: alpha-synuclein endoplasmic-reticulum disease autophagy deficiency huntingtin localization trafficking complexes transport Life Sciences & Biomedicine - Other Topics
 Abstract: The autophagy-lysosomal pathway is impaired in many neurode-generative diseases characterized by protein aggregation, but the link between aggregation and lysosomal dysfunction remains poorly understood. Here, we combine cryo-electron tomography, proteomics, and cell biology studies to investigate the effects of protein aggregates in primary neurons. We use artificial amyloid-like beta-sheet proteins (beta proteins) to focus on the gain-of-function aspect of aggregation. These proteins form fibrillar aggregates and cause neurotoxicity. We show that late stages of autophagy are impaired by the aggregates, resulting in lysosomal alterations reminiscent of lysosomal storage disorders. Mechanistically, beta proteins interact with and sequester AP-3 mu 1, a subunit of the AP-3 adaptor complex involved in protein trafficking to lysosomal organelles. This leads to destabilization of the AP-3 complex, missorting of AP-3 cargo, and lysosomal defects. Restoring AP-3 mu 1 expression ameliorates neurotoxicity caused by beta proteins. Altogether, our results highlight the link between protein aggregation, lysosomal impairments, and neurotoxicity.

Details

show
hide
Language(s): eng - English
 Dates: 2021-12-21
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: Other: WOS:000734893800001
DOI: 10.26508/lsa.202101185
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: Life science alliance
  Abbreviation : Life Sci Alliance
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: Heidelberg : EMBO Press
Pages: - Volume / Issue: 5 (3) Sequence Number: e202101185 Start / End Page: - Identifier: ISSN: 2575-1077
CoNE: https://pure.mpg.de/cone/journals/resource/2575-1077