Endoplasmic reticulum, oxidative stress and their complex crosstalk in neurodegeneration: proteostasis, signaling pathways and molecular chaperones

Giulia Ambrosi; Pamela Milani; Giulia Ambrosi; Pamela Milani

doi:10.3934/molsci.2017.4.424

AIMS Molecular Science

2017, Volume 4, Issue 4: 424-444. doi: 10.3934/molsci.2017.4.424

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Endoplasmic reticulum, oxidative stress and their complex crosstalk in neurodegeneration: proteostasis, signaling pathways and molecular chaperones

Giulia Ambrosi ¹,
Pamela Milani ^{2
,
,}

1.
Translational Pharmacology Department, Drug Design & Discovery, Center of Drug Discovery & Development, Aptuit S.r.l., via Fleming 4, 37135 Verona, Italy
2.
383 King Street, 94158 San Francisco, CA, United States of America

Received: 03 August 2017 Accepted: 09 October 2017 Published: 20 September 2017

Cellular stress caused by protein misfolding, aggregation and redox imbalance is typical of neurodegenerative disorders such as Parkinson’s disease (PD) and Amyotrophic Lateral Sclerosis (ALS). Activation of quality control systems, including endoplasmic reticulum (ER)-mediated degradation, and reactive oxygen species (ROS) production are initially aimed at restoring homeostasis and preserving cell viability. However, persistent damage to macromolecules causes chronic cellular stress which triggers more extreme responses such as the unfolded protein response (UPR) and non-reversible oxidation of cellular components, eventually leading to inflammation and apoptosis. Cell fate depends on the intensity and duration of stress responses converging on the activation of transcription factors involved in the expression of antioxidant, autophagic and lysosome-related genes, such as erythroid-derived 2-related factor 2 (Nrf2) and transcription factor EB respectively. In addition, downstream signaling pathways controlling metabolism, cell survival and inflammatory processes, like mitogen activated protein kinase and nuclear factor-kB, have a key impact on the overall outcome.
Molecular chaperones and ER stress modulators play a critical role in protein folding, in the attenuation of UPR and preservation of mitochondrial and lysosomal activity. Therefore, the use of chaperone molecules is an attractive field of investigation for the development of novel therapeutic strategies and disease-modifying drugs in the context of neurodegenerative diseases such as PD and ALS.
- Parkinson’s Disease,
- Amyotrophic Lateral Sclerosis,
- endoplasmic reticulum,
- oxidative stress,
- MAPK,
- NFkB,
- autophagy,
- molecular chaperones
Citation: Giulia Ambrosi, Pamela Milani. Endoplasmic reticulum, oxidative stress and their complex crosstalk in neurodegeneration: proteostasis, signaling pathways and molecular chaperones[J]. AIMS Molecular Science, 2017, 4(4): 424-444. doi: 10.3934/molsci.2017.4.424

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Abstract

Cellular stress caused by protein misfolding, aggregation and redox imbalance is typical of neurodegenerative disorders such as Parkinson’s disease (PD) and Amyotrophic Lateral Sclerosis (ALS). Activation of quality control systems, including endoplasmic reticulum (ER)-mediated degradation, and reactive oxygen species (ROS) production are initially aimed at restoring homeostasis and preserving cell viability. However, persistent damage to macromolecules causes chronic cellular stress which triggers more extreme responses such as the unfolded protein response (UPR) and non-reversible oxidation of cellular components, eventually leading to inflammation and apoptosis. Cell fate depends on the intensity and duration of stress responses converging on the activation of transcription factors involved in the expression of antioxidant, autophagic and lysosome-related genes, such as erythroid-derived 2-related factor 2 (Nrf2) and transcription factor EB respectively. In addition, downstream signaling pathways controlling metabolism, cell survival and inflammatory processes, like mitogen activated protein kinase and nuclear factor-kB, have a key impact on the overall outcome.
Molecular chaperones and ER stress modulators play a critical role in protein folding, in the attenuation of UPR and preservation of mitochondrial and lysosomal activity. Therefore, the use of chaperone molecules is an attractive field of investigation for the development of novel therapeutic strategies and disease-modifying drugs in the context of neurodegenerative diseases such as PD and ALS.

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