Circulating hsa-miR-323b-3p in Huntington's Disease: A Pilot Study

Abstract

The momentum of gene therapy in Huntington's disease (HD) deserves biomarkers from easily accessible fluid. We planned a study to verify whether plasma miRNome may provide useful peripheral “reporter(s)” for the management of HD patients. We performed an exploratory microarray study of whole non-coding RNA profiles in plasma from nine patients with HD and 13 matched controls [eight healthy subjects (HS) and five psychiatric patients (PP) to minimize possible iatrogenic impact on the profile of non-coding RNAs]. We found an HD-specific signature: downregulation of hsa-miR-98 (fold change, −1.5, p = 0.0338 HD vs. HS, and fold change, 1.5, p = 0.0045 HD vs. PP) and upregulation of hsa-miR-323b-3p (fold change, 1.5, p = 0.0007 HD vs. HS, and fold change, 1.5, p = 0.0111 HD vs. PP). To validate this result in an independent cohort, we quantify by digital droplet PCR (ddPCR) the presence of the two microRNA in the plasma of 33 HD patients and 49 matched controls (25 HS and 24 PP patients). We were able to confirm that hsa-miR-323b-3p was upregulated in HD and premanifest HD vs. HS and PP: the median values (first–third quartile) were 4.1 (0.9–10.53) and 5.8 (1.9–10.70) vs. 0.69 (0.3–2.75) and 1.4 (0.78–2.70), respectively, p < 0.05. No significant difference was found for hsa-miR-98. To evaluate the biological plausibility of the hsa-miR-323b-3p as a component of the disease pathophysiology, we performed a bioinformatic analysis based on its targetome and the huntingtin (HTT) interactome. We found a statistically significant overconnectivity between the targetome of hsa-miR-323b-3p and the HTT interactome (p = 1.48e−08). Furthermore, there was a significant transcription regulation of the HTT interactome by the miR-323b-3p targetome (p = 0.02). The availability of handy, reproducible, and minimally invasive biomarkers coming from peripheral miRNome may be valuable to characterize the illness progression, to indicate new therapeutic targets, and to monitor the effect of disease-modifying treatments. Our data deserve further studies with larger sample size and longitudinal design.

Circulating U13 small nucleolar RNA as a candidate biomarker for Huntington’s disease

“…Recent studies on small non-coding RNAs in plasma from HD patients led to several investigations on circulating micro-RNAs (miRNA) 10–12 . Our recent work found that hsa-miR-323b-3p was upregulated in individuals with mHTT mutation 13 . In this context, we obtained results on small nucleolar RNAs (snoRNA), that were not previously studied in HD; we considered both snoRNAs predictive significance as biomarkers and their possible role in disease pathogenesis.…”

Using Machine Learning to identify microRNA biomarkers for predisposition to Huntington’s Disease

“…Processed samples were downloaded from GSE167630, GSE108395 and GSE108396 (Dong & Scherzer Clemens 2019; Ferraldeschi et al 2021). Each were adult-onset HD vs adult control datasets which were either created using human miRNA specific microarrays or microRNA-seq.…”

A Glimpse of Molecular Biomarkers in Huntington’s Disease

“…In the case of HD, variations in circulating miR-10b-5p and miR-486-5p in plasma resemble those observed in brain miRNAs [ 127 ], certain miRNAs (miR-122-5p, miR-100-5p, miR-641 and miR-330-3p) can be associated with the functional capabilities of patients [ 128 ], and their levels can be modified after diet-based interventions (e.g., miR-338-3p, miR-128-3p, miR-23a-3p and miR-24-3p [ 129 ]). Other miRNAs have been found to be different between HD patients and healthy controls (e.g., miR-34b and miR-323b-3p [ 130 , 131 ]). However, these RNA species also suffer the same challenges of reproducibility and validation of mRNAs.…”