Cited by 142Alzheimer's disease research and treatmentsPrion Diseases and Protein MisfoldingAmyotrophic Lateral Sclerosis Research

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Mechanisms of protein toxicity in neurodegenerative diseases

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Chung, Chang Geon, Lee, Hyosang, Lee, Sung Bae·2018·Cellular and Molecular Life Sciences

DOI 10.1007/s00018-018-2854-4PMC PMC6063327

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Abstract

Protein toxicity can be defined as all the pathological changes that ensue from accumulation, mis-localization, and/or multimerization of disease-specific proteins. Most neurodegenerative diseases manifest protein toxicity as one of their key pathogenic mechanisms, the details of which remain unclear. By systematically deconstructing the nature of toxic proteins, we aim to elucidate and illuminate some of the key mechanisms of protein toxicity from which therapeutic insights may be drawn. In this review, we focus specifically on protein toxicity from the point of view of various cellular compartments such as the nucleus and the mitochondria. We also discuss the cell-to-cell propagation of toxic disease proteins that complicates the mechanistic understanding of the disease progression as well as the spatiotemporal point at which to therapeutically intervene. Finally, we discuss selective neuronal vulnerability, which still remains largely enigmatic.

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Fig. 1 A schematic overview of protein toxicity. Accumulation of toxic disease proteins is shown to induce dysfunctions in specified compartments such as the nucleus, mitochondria, cytoplasm, and stress granules. They can also propagate into other nearby cells, spreading the disease pathologyCC BY · PubMed Central

Fig. 2 Propagation of misfolded proteins via intercellular transmission. Gradual change in the distribution of α-synuclein (a) and tau (b) inclusions in the brains of patients suffering from Parkinson’s (a) and Alzheimer’s (b) diseases. c Intercellular transmission of misfolded proteins via exocytosis, endocytosis, exosomes, and tunneling nanotubesCC BY · PubMed Central

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“The buildup of neurotoxic agents is believed to cause neuronal damage and death, which can ultimately lead to various forms of neurological dysfunction that include cognitive decline, motor abnormalities, mental disorders, and loss of inhibition (Chung et al., 2018; Taylor et al., 2002; Vickers et al., 2009).”

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Authors: Chung, C. G., Lee, H., & Lee, S. B.
Affiliations: Daegu Gyeongbuk Institute of Science and Technology (KR)
Corresponding author: Lee, Hyosang
Lee, Sung Bae
ORCID: Chung, Chang Geon
Lee, Hyosang
Lee, Sung Bae
Venue: Cellular and Molecular Life Sciences
Publisher: Springer Science and Business Media LLC
Published: 2018-06-12
Volume: 75
Issue: 17
Pages: 3159-3180
ISSN: 1420-682X (ISSN-L)
1420-9071
DOI: 10.1007/s00018-018-2854-4
PMC: PMC6063327
OpenAlex: W2807962932
Cited by: 142
References: 246
Citations by year: 2026: 7 · 2025: 20 · 2024: 13 · 2023: 18 · 2022: 21 · 2021: 30 · 2020: 23 · 2019: 8 · 2018: 1
FWCI: 2.03
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (tdm)
Locations: Cellular and Molecular Life Sciences (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: Ministry of Science and ICT (18-BD-0402, 18-BT-02, 18-01-HRSS-02, 18-BR-04-03)
Ministry of Science, ICT and Future Planning (2017R1A2B4003351, 2016M3C7A1947307, 2016M3C7A1904148)
Korea Research Institute of Standards and Science (KRISS-2018-GP2018-0018)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
Keywords: protein toxicity, neurodegenerative diseases, protein aggregation, protein mislocalization, protein oligomerization, mitochondrial toxicity, cell-to-cell transmission, selective neuronal vulnerability, disease progression, therapeutic interventions
MeSH terms: Animals, Cell Nucleus, Humans, Mitochondria, Neurons, Proteins, Disease Progression, Neurodegenerative Diseases

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Mechanisms of protein toxicity in neurodegenerative diseases

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