From Posttranslational Modifications to Disease Phenotype: A Substrate Selection Hypothesis in Neurodegenerative Diseases
A number of neurodegenerative diseases including prion diseases, tauopathies and synucleinopathies exhibit multiple clinical phenotypes. A diversity of clinical phenotypes has been attributed to the ability of amyloidogenic proteins associated with a particular disease to acquire multiple, conformat...
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doaj-8edc31284f5a4822abd2e154606cec6d2021-01-19T00:01:15ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-01-012290190110.3390/ijms22020901From Posttranslational Modifications to Disease Phenotype: A Substrate Selection Hypothesis in Neurodegenerative DiseasesIlia V. Baskakov0Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201, USAA number of neurodegenerative diseases including prion diseases, tauopathies and synucleinopathies exhibit multiple clinical phenotypes. A diversity of clinical phenotypes has been attributed to the ability of amyloidogenic proteins associated with a particular disease to acquire multiple, conformationally distinct, self-replicating states referred to as strains. Structural diversity of strains formed by tau, α-synuclein or prion proteins has been well documented. However, the question how different strains formed by the same protein elicit different clinical phenotypes remains poorly understood. The current article reviews emerging evidence suggesting that posttranslational modifications are important players in defining strain-specific structures and disease phenotypes. This article put forward a new hypothesis referred to as substrate selection hypothesis, according to which individual strains selectively recruit protein isoforms with a subset of posttranslational modifications that fit into strain-specific structures. Moreover, it is proposed that as a result of selective recruitment, strain-specific patterns of posttranslational modifications are formed, giving rise to unique disease phenotypes. Future studies should define whether cell-, region- and age-specific differences in metabolism of posttranslational modifications play a causative role in dictating strain identity and structural diversity of strains of sporadic origin.https://www.mdpi.com/1422-0067/22/2/901prion proteintauα-synucleinneurodegenerative diseasesprion diseaseAlzheimer’s diseases |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ilia V. Baskakov |
spellingShingle |
Ilia V. Baskakov From Posttranslational Modifications to Disease Phenotype: A Substrate Selection Hypothesis in Neurodegenerative Diseases International Journal of Molecular Sciences prion protein tau α-synuclein neurodegenerative diseases prion disease Alzheimer’s diseases |
author_facet |
Ilia V. Baskakov |
author_sort |
Ilia V. Baskakov |
title |
From Posttranslational Modifications to Disease Phenotype: A Substrate Selection Hypothesis in Neurodegenerative Diseases |
title_short |
From Posttranslational Modifications to Disease Phenotype: A Substrate Selection Hypothesis in Neurodegenerative Diseases |
title_full |
From Posttranslational Modifications to Disease Phenotype: A Substrate Selection Hypothesis in Neurodegenerative Diseases |
title_fullStr |
From Posttranslational Modifications to Disease Phenotype: A Substrate Selection Hypothesis in Neurodegenerative Diseases |
title_full_unstemmed |
From Posttranslational Modifications to Disease Phenotype: A Substrate Selection Hypothesis in Neurodegenerative Diseases |
title_sort |
from posttranslational modifications to disease phenotype: a substrate selection hypothesis in neurodegenerative diseases |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-01-01 |
description |
A number of neurodegenerative diseases including prion diseases, tauopathies and synucleinopathies exhibit multiple clinical phenotypes. A diversity of clinical phenotypes has been attributed to the ability of amyloidogenic proteins associated with a particular disease to acquire multiple, conformationally distinct, self-replicating states referred to as strains. Structural diversity of strains formed by tau, α-synuclein or prion proteins has been well documented. However, the question how different strains formed by the same protein elicit different clinical phenotypes remains poorly understood. The current article reviews emerging evidence suggesting that posttranslational modifications are important players in defining strain-specific structures and disease phenotypes. This article put forward a new hypothesis referred to as substrate selection hypothesis, according to which individual strains selectively recruit protein isoforms with a subset of posttranslational modifications that fit into strain-specific structures. Moreover, it is proposed that as a result of selective recruitment, strain-specific patterns of posttranslational modifications are formed, giving rise to unique disease phenotypes. Future studies should define whether cell-, region- and age-specific differences in metabolism of posttranslational modifications play a causative role in dictating strain identity and structural diversity of strains of sporadic origin. |
topic |
prion protein tau α-synuclein neurodegenerative diseases prion disease Alzheimer’s diseases |
url |
https://www.mdpi.com/1422-0067/22/2/901 |
work_keys_str_mv |
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