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Methods to Study Changes in Inherent Protein Aggregation with Age in Caenorhabditis elegans
Published on: November 26, 2017
+1 Proteins and aging
F W van Leeuwen1, L Gerez, R Benne
1Graduate School Neurosciences Amsterdam, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ, Amsterdam, The Netherlands.
Abstract:
Molecular misreading is an expression used to describe errors in RNA that lead to the translation of mutated proteins. We have shown that dinucleotide deletions (delta GA, delta GU) are introduced in simple sequence repeats (e.g. GAGAG) of mRNA. If the resulting mutant transcripts escape RNA quality control systems, they are translated into +1 proteins. If functional domains are located downstream of the frameshift site, the result will be a protein with either a partial or complete loss of function. A clear example is ubiquitin(+1) (UBB(+1)), which has lost its capacity to ubiquitinate, i.e. tagging proteins destined for proteasomal degradation. This is an important step in regulating the degradation of misfolded proteins and transcription factors. In fact, UBB(+1) seems to block the proteasome. UBB(+1) and other proteins accumulate in the neuropathological hallmarks of Alzheimer's disease (AD), which suggests a causal relationship. We have hypothesized that quality control mechanisms for both transcripts and proteins work less efficiently during aging. In this manner +1 proteins may become manifest and contribute to age-related diseases.
Insights
Errors in RNA, called molecular misreading, can create mutated proteins. These +1 proteins, like ubiquitin(+1), may accumulate with aging and contribute to diseases such as Alzheimer's disease.
Area of Science:
- Molecular Biology
- Genetics
- Neuroscience
Background:
- Molecular misreading generates errors in RNA, leading to mutated protein production.
- Dinucleotide deletions in mRNA simple sequence repeats can cause frameshift mutations during translation.
- These errors result in the synthesis of '+1' proteins, which may have altered or lost function.
Purpose of the Study:
- To investigate the phenomenon of molecular misreading and its consequences.
- To explore the role of '+1' proteins, such as ubiquitin(+1) (UBB(+1)), in cellular processes.
- To hypothesize the link between impaired quality control, '+1' protein accumulation, and age-related diseases like Alzheimer's disease (AD).
Main Methods:
- Analysis of mRNA sequences for dinucleotide deletions in simple sequence repeats.
- Investigation of the functional consequences of '+1' protein production, using UBB(+1) as a model.
- Examination of the accumulation of '+1' proteins in neuropathological hallmarks of AD.
Main Results:
- Dinucleotide deletions (delta GA, delta GU) were identified in mRNA simple sequence repeats.
- The resulting '+1' proteins, exemplified by UBB(+1), exhibit loss of function (e.g., impaired ubiquitination).
- UBB(+1) accumulation was observed in Alzheimer's disease pathology, suggesting a potential role in the disease.
Conclusions:
- Molecular misreading can produce non-functional '+1' proteins that escape quality control.
- Impaired RNA and protein quality control during aging may lead to the manifestation of '+1' proteins.
- Accumulation of '+1' proteins, such as UBB(+1), is implicated in the pathogenesis of age-related diseases, including Alzheimer's disease.
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