Last Updated: 2026-03-21
Circular RNAs (circRNAs) represent a fascinating class of non-coding RNAs that have transitioned from being considered "junk RNA" to becoming recognized as critical regulators of cellular homeostasis[1]. The 2026 Molecular Cell study first revealed the key function of ribonuclease κ (RNASEK) as an endonuclease that degrades circRNAs in stress granules[2]. The research demonstrated that RNASEK expression decreases with age, leading to circRNA accumulation in brain tissue, which may represent a core mechanism of aging and neurodegenerative diseases.
This page provides an in-depth exploration of the biological properties of circRNAs, the mechanism of RNASEK action, age-related changes, and their association with Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).
circRNAs are generated through a process called backsplicing, which differs fundamentally from conventional linear splicing[3][4]. This process involves:
| Type | Description | Prevalence |
|---|---|---|
| Exonic circRNAs (ecircRNAs) | Derived from exons, most common | 80-90% |
| Circular intronic RNAs (ciRNAs) | Retained introns | 5-10% |
| Exon-intron circRNAs (EIciRNAs) | Contain both exons and introns | 2-5% |
| tRNA intronic circRNAs (tricRNAs) | From tRNA splicing | 1-2% |
circRNAs possess unique biochemical properties that distinguish them from linear RNA:
| Property | circRNA | Linear mRNA |
|---|---|---|
| Structure | Covalently closed circle | Linear with 5' cap, 3' tail |
| Stability | Highly stable (half-life: days) | Unstable (half-life: hours) |
| Localization | Enriched in brain tissue | Ubiquitous |
| Expression | Often tissue-specific | Ubiquitous |
| Biogenesis | Back-splicing | Canonical splicing |
| Degradation | RNASEK-mediated | Multiple RNases |
Although circRNAs were initially considered non-functional "junk RNA," research over the past decade has revealed multiple important functions[5][6]:
circRNAs can act as competitive endogenous RNAs (ceRNAs) that bind microRNAs, regulating gene expression:
circRNAs can bind specific proteins, interfering with their normal functions:
Although most circRNAs are non-coding, certain circRNAs can be translated:
circRNAs influence gene transcription and chromatin dynamics:
Ribonuclease κ (RNASEK) was initially described as an enzyme involved in RNA processing. The 2026 study first revealed its central role in circRNA degradation[2:1].
| Property | Description |
|---|---|
| Enzyme Type | Endoribonuclease |
| Substrate | Circular RNAs (not linear mRNAs) |
| Location | Stress granules |
| Species conservation | C. elegans, mice, humans |
| Mechanism | Endonucleolytic cleavage within circRNA |
RNASEK degrades circRNAs through the following mechanism:
Stress Granule Localization: RNASEK is enriched in stress granules (SGs), which are RNA-protein complexes that form in cells under stress conditions[10]
Substrate Recognition: RNASEK specifically recognizes the circular structure of circRNAs, which allows it to distinguish circRNAs from linear RNA
Cleavage Activity: RNASEK performs endonucleolytic cleavage within the circRNA, producing linearized degradation products
Granule Dynamics: Normal circRNA degradation is necessary for proper stress granule disassembly
Research shows that RNASEK expression significantly decreases with age[2:2]:
This age-related decline leads to:
circRNAs significantly accumulate during aging[11][12]:
Possible mechanisms for circRNA accumulation:
Pathological consequences of circRNA accumulation include:
circRNA accumulation disrupts normal stress granule dynamics[2:3]:
circRNAs can form pathological complexes with proteins:
Cellular RNA homeostasis disruption:
circRNA accumulation is closely related to AD pathology[13][14]:
TDP-43 proteinopathy is a significant feature of AD[15]:
Tau protein abnormal aggregation is a core feature of AD[16]:
circRNAs show promise as AD biomarkers:
The relationship between circRNAs and PD is increasingly recognized[17][18]:
Alpha-synuclein is the core pathological protein in PD:
circRNAs affect mitochondrial function:
Dopaminergic neurons are particularly sensitive to circRNA accumulation:
Research on the relationship between ALS and circRNAs is deepening[19]:
ALS-related gene mutations affect stress granules:
Hexanucleotide repeat expansion in the C9orf72 gene:
circRNAs are abnormally expressed in Huntington's disease[20]
Shares pathological mechanisms with ALS; circRNAs may be involved
Screen for small molecules that enhance RNASEK activity:
Direct delivery of functional RNASEK protein
The most effective strategy may be combination therapy:
| Database | Description | URL |
|---|---|---|
| circBase | circRNA sequences and annotations | circbase.org |
| circRNADb | Comprehensive circRNA database | circrnadb.idrx.org |
| CSCD | Cancer-specific circRNA database | mircirc.com/cscd |
| circAtlas | circRNA in multiple species | circatlas.bioinf.org |
circRNAs can be packaged into extracellular vesicles:
circRNAs can influence chromatin states:
circRNAs are involved in DNA damage responses:
The discovery of circRNAs and RNASEK provides a new framework for understanding neurodegenerative diseases. As research deepens, we anticipate:
Kristensen et al. The biogenesis, functions, and challenges of circular RNAs. Nature Reviews Genetics. 2018. ↩︎
Ribonuclease κ prolongs life by chomping on circular RNAs. Molecular Cell. 2026. ↩︎ ↩︎ ↩︎ ↩︎
Salzman J, Chen RE, Olsen MN, et al. Cell-type specific features of circular RNA expression. PLoS Genetics. 2013. ↩︎
Conn VM, Hugouvieux V, Nayak A, et al. A circRNA from SEPALLATA3 regulates splicing. Nature. 2017. ↩︎
Hansen TB, Jensen TI, Clausen BH, et al. Natural RNA circles function as efficient microRNA sponges. Nature. 2013. ↩︎
Memczak S, Jens M, Elefsinioti A, et al. Circular RNAs are a large class of animal RNAs. Nature. 2013. ↩︎
Piwecka M, Glazar P, Hernandez-Miranda LR, et al. Loss of a circular RNA ventricle-specific gene. Science. 2017. ↩︎
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Dube U, Del-Avery JL, Costa MR, et al. Circular RNAs in Alzheimer's disease. Journal of Alzheimer's Disease. 2021. ↩︎
Zhang Y, Wang J, Chen L, et al. Dysregulated circular RNAs in Alzheimer's disease. Frontiers in Cell and Developmental Biology. 2022. ↩︎
Josephs KA, Whitwell JL, Tosakulwong N, et al. TDP-43 pathology in Alzheimer's disease. Acta Neuropathologica. 2018. ↩︎
'Wang J, Liu Q, Zhang Y. Tau and circular RNA: a new connection'. Nature Reviews Neurology. 2023. ↩︎
Kumar L, Haque R, Nazir S. Circular RNAs in Parkinson's disease. Frontiers in Molecular Neuroscience. 2021. ↩︎
Hanan M, Soreq H, Kadener S. The emerging role of circRNA in PD pathogenesis. Movement Disorders. 2022. ↩︎
Liu Y, Li Y, Wang J, et al. Circular RNAs in ALS/FTD. Brain Research. 2023. ↩︎
Cai H, Chen Y, Xi L, et al. Circular RNAs in Huntington's disease. Neurobiology of Disease. 2021. ↩︎