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Biological Spectrum of Amyotrophic Lateral Sclerosis Prions


Polymenidou, Magdalini; Cleveland, Don W (2017). Biological Spectrum of Amyotrophic Lateral Sclerosis Prions. Cold Spring Harbor Perspectives in Medicine, 7(11):a024133.

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD) are two neurodegenerative diseases with distinct clinical features but common genetic causes and neuropathological signatures. Ten years after the RNA-binding protein TDP-43 was discovered as the main protein in the cytoplasmic inclusions that characterize ALS and FTLD, their pathogenic mechanisms have never seemed more complex. Indeed, discoveries of the past decade have revolutionized our understanding of these diseases, highlighting their genetic heterogeneity and the involvement of protein-RNA assemblies in their pathogenesis. Importantly, these assemblies serve as the foci of protein misfolding and mature into insoluble structures, which further recruit native proteins, turning them into misfolded forms. This self-perpetuating mechanism is a twisted version of classical prion replication that leads to amplification of pathological protein complexes that spread throughout the neuraxis, offering a pathogenic principle that underlies the rapid disease progression that characterizes ALS and FTLD.

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD) are two neurodegenerative diseases with distinct clinical features but common genetic causes and neuropathological signatures. Ten years after the RNA-binding protein TDP-43 was discovered as the main protein in the cytoplasmic inclusions that characterize ALS and FTLD, their pathogenic mechanisms have never seemed more complex. Indeed, discoveries of the past decade have revolutionized our understanding of these diseases, highlighting their genetic heterogeneity and the involvement of protein-RNA assemblies in their pathogenesis. Importantly, these assemblies serve as the foci of protein misfolding and mature into insoluble structures, which further recruit native proteins, turning them into misfolded forms. This self-perpetuating mechanism is a twisted version of classical prion replication that leads to amplification of pathological protein complexes that spread throughout the neuraxis, offering a pathogenic principle that underlies the rapid disease progression that characterizes ALS and FTLD.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Quantitative Biomedicine
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > General Biochemistry, Genetics and Molecular Biology
Uncontrolled Keywords:General Biochemistry, Genetics and Molecular Biology, General Medicine
Language:English
Date:1 November 2017
Deposited On:01 Nov 2021 14:29
Last Modified:02 Nov 2021 21:01
Publisher:Cold Spring Harbor Laboratory Press
ISSN:2157-1422
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1101/cshperspect.a024133

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