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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Amyloid-like aggregating proteins cause lysosomal defects in neurons via gain-of-function toxicity. / Riera-Tur, Irene; Schäfer, Tillman; Hornburg, Daniel; Mishra, Archana; da Silva Padilha, Miguel; Fernández-Mosquera, Lorena; Feigenbutz, Dennis; Auer, Patrick; Mann, Matthias; Baumeister, Wolfgang; Klein, Rüdiger; Meissner, Felix; Raimundo, Nuno; Fernández-Busnadiego, Rubén; Dudanova, Irina.

In: Life Science Alliance, Vol. 5, No. 3, 03.2022.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Riera-Tur, I, Schäfer, T, Hornburg, D, Mishra, A, da Silva Padilha, M, Fernández-Mosquera, L, Feigenbutz, D, Auer, P, Mann, M, Baumeister, W, Klein, R, Meissner, F, Raimundo, N, Fernández-Busnadiego, R & Dudanova, I 2022, 'Amyloid-like aggregating proteins cause lysosomal defects in neurons via gain-of-function toxicity', Life Science Alliance, vol. 5, no. 3. https://doi.org/10.26508/lsa.202101185

APA

Riera-Tur, I., Schäfer, T., Hornburg, D., Mishra, A., da Silva Padilha, M., Fernández-Mosquera, L., Feigenbutz, D., Auer, P., Mann, M., Baumeister, W., Klein, R., Meissner, F., Raimundo, N., Fernández-Busnadiego, R., & Dudanova, I. (2022). Amyloid-like aggregating proteins cause lysosomal defects in neurons via gain-of-function toxicity. Life Science Alliance, 5(3). https://doi.org/10.26508/lsa.202101185

Vancouver

Riera-Tur I, Schäfer T, Hornburg D, Mishra A, da Silva Padilha M, Fernández-Mosquera L et al. Amyloid-like aggregating proteins cause lysosomal defects in neurons via gain-of-function toxicity. Life Science Alliance. 2022 Mar;5(3). https://doi.org/10.26508/lsa.202101185

Author

Riera-Tur, Irene ; Schäfer, Tillman ; Hornburg, Daniel ; Mishra, Archana ; da Silva Padilha, Miguel ; Fernández-Mosquera, Lorena ; Feigenbutz, Dennis ; Auer, Patrick ; Mann, Matthias ; Baumeister, Wolfgang ; Klein, Rüdiger ; Meissner, Felix ; Raimundo, Nuno ; Fernández-Busnadiego, Rubén ; Dudanova, Irina. / Amyloid-like aggregating proteins cause lysosomal defects in neurons via gain-of-function toxicity. In: Life Science Alliance. 2022 ; Vol. 5, No. 3.

Bibtex

@article{b13328ff671a4f00b1702594cc034783,
title = "Amyloid-like aggregating proteins cause lysosomal defects in neurons via gain-of-function toxicity",
abstract = "The autophagy-lysosomal pathway is impaired in many neurodegenerative 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 β-sheet proteins (β 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, β proteins interact with and sequester AP-3 μ1, 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-3μ1 expression ameliorates neurotoxicity caused by β proteins. Altogether, our results highlight the link between protein aggregation, lysosomal impairments, and neurotoxicity.",
keywords = "Amyloid beta-Peptides/genetics, Amyloidogenic Proteins/genetics, Cell Survival/genetics, Gain of Function Mutation, Gene Expression, Lysosomes/metabolism, Neurodegenerative Diseases/etiology, Neurons/metabolism, Protein Aggregates, Protein Aggregation, Pathological/metabolism, Signal Transduction",
author = "Irene Riera-Tur and Tillman Sch{\"a}fer and Daniel Hornburg and Archana Mishra and {da Silva Padilha}, Miguel and Lorena Fern{\'a}ndez-Mosquera and Dennis Feigenbutz and Patrick Auer and Matthias Mann and Wolfgang Baumeister and R{\"u}diger Klein and Felix Meissner and Nuno Raimundo and Rub{\'e}n Fern{\'a}ndez-Busnadiego and Irina Dudanova",
note = "{\textcopyright} 2021 Riera-Tur et al.",
year = "2022",
month = mar,
doi = "10.26508/lsa.202101185",
language = "English",
volume = "5",
journal = "Life Science Alliance",
issn = "2575-1077",
publisher = "Life Science Alliance",
number = "3",

}

RIS

TY - JOUR

T1 - Amyloid-like aggregating proteins cause lysosomal defects in neurons via gain-of-function toxicity

AU - Riera-Tur, Irene

AU - Schäfer, Tillman

AU - Hornburg, Daniel

AU - Mishra, Archana

AU - da Silva Padilha, Miguel

AU - Fernández-Mosquera, Lorena

AU - Feigenbutz, Dennis

AU - Auer, Patrick

AU - Mann, Matthias

AU - Baumeister, Wolfgang

AU - Klein, Rüdiger

AU - Meissner, Felix

AU - Raimundo, Nuno

AU - Fernández-Busnadiego, Rubén

AU - Dudanova, Irina

N1 - © 2021 Riera-Tur et al.

PY - 2022/3

Y1 - 2022/3

N2 - The autophagy-lysosomal pathway is impaired in many neurodegenerative 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 β-sheet proteins (β 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, β proteins interact with and sequester AP-3 μ1, 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-3μ1 expression ameliorates neurotoxicity caused by β proteins. Altogether, our results highlight the link between protein aggregation, lysosomal impairments, and neurotoxicity.

AB - The autophagy-lysosomal pathway is impaired in many neurodegenerative 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 β-sheet proteins (β 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, β proteins interact with and sequester AP-3 μ1, 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-3μ1 expression ameliorates neurotoxicity caused by β proteins. Altogether, our results highlight the link between protein aggregation, lysosomal impairments, and neurotoxicity.

KW - Amyloid beta-Peptides/genetics

KW - Amyloidogenic Proteins/genetics

KW - Cell Survival/genetics

KW - Gain of Function Mutation

KW - Gene Expression

KW - Lysosomes/metabolism

KW - Neurodegenerative Diseases/etiology

KW - Neurons/metabolism

KW - Protein Aggregates

KW - Protein Aggregation, Pathological/metabolism

KW - Signal Transduction

U2 - 10.26508/lsa.202101185

DO - 10.26508/lsa.202101185

M3 - Journal article

C2 - 34933920

VL - 5

JO - Life Science Alliance

JF - Life Science Alliance

SN - 2575-1077

IS - 3

ER -

ID: 303114575