The Hidden Layer of Control
Genes are not simply "on" or "off." Their output is fine-tuned by a vast regulatory network, a key part of which involves microRNAs (miRNAs). These small, non-coding RNA molecules bind to messenger RNA (mRNA) and prevent it from being translated into protein. In the case of SHANK3, specific miRNAs act as "molecular brakes," controlling synapse density and plasticity. Dysregulation of these brakes can lead to the synaptic deficits seen in ASD.
Key Players: miR-7, miR-34a, and miR-504
Research has identified several miRNAs that directly target the 3' untranslated region (3'UTR) of
SHANK3 mRNA.
1. **miR-34a:** Often upregulated in neurodegenerative and neurodevelopmental conditions, miR-34a acts as a
repressor. High levels of miR-34a suppress SHANK3 production, leading to synaptic loss.
2. **miR-504 and miR-7:** These miRNAs also negatively regulate SHANK3. Overexpression of miR-504 in
hippocampal neurons has been shown to reduce SHANK3 protein levels and decrease dendritic spine density.
Therapeutic Strategy: Releasing the Brakes
For patients with SHANK3 haploinsufficiency, the goal is to boost the output of the single remaining healthy gene copy. One way to do this is to "release the brakes" imposed by these naturally occurring miRNAs. By using **Antisense Oligonucleotides (ASOs)** or "antagomirs" designed to bind to and inhibit miR-34a or miR-504, we can prevent them from binding to SHANK3 mRNA. This stabilizes the mRNA, allowing more protein to be produced and potentially restoring synaptic function to therapeutic levels.
Biomarkers for Detection
Beyond therapy, miRNAs offer a powerful diagnostic tool. Because they can be detected in blood and other biofluids, altered levels of miR-34a or miR-504 could serve as peripheral biomarkers. This would allow clinicians to identify patients who have a specific "molecular subtype" of autism involving SHANK3 dysregulation, enabling early stratification and personalized treatment planning.
Excerpt from: Harnessing Single-Cell Omics, CRISPR, MSCs, miRNAs, and Valproic Acid Targeting SHANK3 Mutations and Associated Pathways by Peter De Ceuster
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