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Characterizing Histone Post-translational Modification Alterations in Yeast Neurodegenerative Proteinopathy Models
Published on: March 24, 2019
RAN proteins in neurodegenerative disease: Repeating themes and unifying therapeutic strategies
Shu Guo1, Lien Nguyen1, Laura P W Ranum2
1Center for NeuroGenetics, College of Medicine, University of Florida, USA; Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, USA.
Abstract:
Microsatellite-expansion mutations cause >50 neurological diseases but there are no effective treatments. Mechanistic studies have historically focused on protein loss-of-function and protein or RNA gain-of-function effects. It is now clear that many expansion mutations are bidirectionally transcribed producing two toxic expansion RNAs, which can produce up to six mutant proteins by repeat associated non-AUG (RAN) translation. Multiple types of RAN proteins have been shown to be toxic in cell and animal models, to lead to common types of neuropathological changes, and to dysregulate key pathways. How RAN proteins are produced without the canonical AUG or close-cognate AUG-like initiation codons is not yet completely understood but RNA structure, flanking sequences and stress pathways have been shown to be important. Here, we summarize recent progress in understanding the role of RAN proteins, mechanistic insights into their production, and the identification of novel therapeutic strategies that may be applicable across these neurodegenerative disorders.
Insights
Microsatellite-expansion mutations cause neurological diseases. Toxic repeat-associated non-AUG (RAN) translation produces mutant proteins, offering new therapeutic targets for these neurodegenerative disorders.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Microsatellite-expansion mutations are linked to over 50 neurological diseases.
- Current treatments are ineffective, with research historically focusing on protein loss-of-function and RNA gain-of-function.
- Emerging evidence highlights toxic repeat-associated non-AUG (RAN) translation as a key pathogenic mechanism.
Purpose of the Study:
- To review the role of RAN proteins in neurodegenerative diseases.
- To explore mechanistic insights into the production of RAN proteins.
- To identify novel therapeutic strategies for these disorders.
Main Methods:
- Review of recent scientific literature on microsatellite-expansion mutations and RAN translation.
- Analysis of studies on the toxicity and neuropathological effects of RAN proteins.
- Examination of research on factors influencing RAN protein production (RNA structure, flanking sequences, stress pathways).
Main Results:
- Bidirectional transcription of expansion mutations produces toxic RNAs.
- RAN translation can generate up to six different mutant proteins.
- RAN proteins are toxic in cellular and animal models, causing neuropathological changes and pathway dysregulation.
Conclusions:
- RAN proteins play a significant role in the pathogenesis of microsatellite-expansion neurological disorders.
- Understanding the mechanisms of RAN protein production is crucial for therapeutic development.
- Targeting RAN translation presents a promising therapeutic avenue for a range of neurodegenerative diseases.
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