miRNA biomarkers in neurological disorders
| Neurological disorder | Biomarker miRNA(s) | Key findings | References |
|---|---|---|---|
| AD | miR-21-5p | miR-21 was upregulated in the CSF of MCI patients who progressed to AD but not in non-AD MCI, highlighting its discriminatory potential. It was elevated in microglia, neurons, and astrocytes derived from iPSCs of PSEN1ΔE9 AD patients. Neuron-derived exosomes were enriched in miR-21, and astrocyte exosomes showed increased levels after immunostimulation. Its role in microglial activation and astrocyte reactivity was confirmed in 3D hippocampal cultures with SWE cells. | [72] |
| miR-125b-5p | miR-125b-5p was elevated 1.6-fold in AD brains and similarly high in CSF compared to healthy controls. Overexpression increased ERK1/2 activation, promoting tau phosphorylation. Studies comparing AD patients and healthy controls confirmed these findings. Induced miR-125b-5p overexpression in primary hippocampal neurons altered tau phosphatase levels, affecting Bcl-W, DUSP-6, and PP1CA, suggesting its role in AD-related tau pathology.miR-125b-5p promotes tau hyperphosphorylation in AD by reducing DUSP6/PPP1CA (~50%), elevating p-ERK1/2, tau phosphorylation, and kinase activity. Banzhaf-Strathmann (2014) [73] confirmed direct targeting of DUSP6 by miR-125b via luciferase assays, with effects abolished by binding site mutation and reversed by miR-125b inhibition. | [73, 74] | |
| miR-124 | Overexpression in AD neurons and their exosomes. Observed in mouse organotypic hippocampal slices transplanted with SH-SY5Y cells expressing the human APP695 Swedish mutation. | [72] | |
| miR-9-5p | Liu et al. (2020) [75] found that miR-9-5p is decreased in Aβ25-35-induced HT22 cells; its overexpression inhibits mitochondrial dysfunction, oxidative stress, and apoptosis by targeting GSK-3β, suggesting a protective role in AD models. | [75] | |
| PD | miR-133b | miR-133b was significantly downregulated in PD patients (p = 0.006) and linked to neurodegeneration and motor symptoms. Although its correlation with disease severity was not established, reduced levels suggest a potential role in PD. miR-133b and miR-433 were correlated (r = 0.87 and 0.85) but may not predict PD alone. A study by Zhang et al. (2019) [77] demonstrated that miR-133b directly targets the 3′-UTR of α-synuclein mRNA, leading to reduced α-synuclein levels and mitigating dopaminergic neuron injury in PD models. | [76, 77] |
| miR-124 | miR-124 was significantly upregulated in the plasma of PD patients (p < 0.001), suggesting its potential as a biomarker for early detection and disease monitoring. Its increased levels may correlate with cognitive decline and motor dysfunction, highlighting its role in PD progression. | [78] | |
| miR-34b/c | miR-34b/c was downregulated in key brain regions of PD patients, including the substantia nigra and frontal cortex, across Braak stages 1–5. This depletion was linked to mitochondrial dysfunction and oxidative stress. In SH-SY5Y dopaminergic cells, reduced miR-34b/c impaired viability and mitochondrial function, highlighting their therapeutic potential. | [79] | |
| miR-221-3p | miR-221-3p was significantly upregulated in PD patients (1.79-fold increase; p = 0.032) compared to healthy controls, suggesting its potential as a biomarker. It may help differentiate PD from other movement disorders like MSA, highlighting its diagnostic value in neurodegenerative conditions. | [80] | |
| Multiple sclerosis (MS) | miR-181c | miR levels were elevated in the CSF of MS patients compared to those with other neurologic diseases (AUC = 0.75, p < 0.0001). Higher levels were observed in secondary progressive MS (7.08 ± 0.36) than in relapsing-remitting MS (6.97 ± 0.32, p = 0.036) and primary progressive MS (6.89 ± 0.3, p = 0.046). It may indicate inflammatory activity in early MS. | [81] |
| miR-181c and miR-633 | The combination of miR-181c and miR-633 improved diagnostic accuracy for MS. A cutoff of > 6.79 for miR-181c and > 21.53 for miR-633 achieved 62% sensitivity and 89% specificity in distinguishing MS from other neurologic diseases, enhancing its potential as a diagnostic biomarker. | [81, 82] | |
| miR-145 and miR-223 | miR-145 and miR-223 were significantly upregulated in MS patients compared to healthy controls. In relapsing-remitting MS, fold changes were 2.6 and 2.7, respectively, while in secondary progressive MS, they were 1.4 and 2.2. This suggests their potential role in disease progression and as biomarkers for distinguishing MS subtypes. | [83] | |
| ALS | miR-132-5p | CSF levels of miR-132 and miR-9 were downregulated in ALS patients, particularly those with TARDBP, FUS, and C9orf72 mutations, but not in SOD1 cases. Plasma deregulation distinguished symptomatic from asymptomatic TARDBP-ALS mutation carriers. Increased peripheral expression in symptomatic subjects was observed, but not statistically significant. qPCR analysis confirmed these findings in ALS patients and healthy controls. | [84] |
| miR-155 and miR-124-3p | Cunha et al. (2018) [85] demonstrated that miR-155 is significantly upregulated in the early, pre-symptomatic phase of ALS in both SOD1G93A mouse models and patient-derived samples. In contrast, miR-124-3p, a miRNA with key roles in maintaining neuronal identity and suppressing microglial activation, was found to be upregulated predominantly during the symptomatic phase of ALS. | [85] | |
| Huntington’s disease (HD) | miR-34b | miR-34b was significantly elevated in asymptomatic HD patients, correlating with mutant huntingtin protein levels in neuronal and pluripotent cells. | [86] |
| miR-34a-5p | miR-34a-5p was deregulated in the R6/2 mouse model and human HD brain tissues, interacting with multiple HD-associated genes. Direct binding to 3′-UTRs of TAF4B, NDUFA9, HIP1, and NRF1 was confirmed via mutagenesis and protein analysis. HiTmIR identified additional targets, linking miR-34a-5p to pathways like glutamine receptor signaling and calcium ion transport. | [87] | |
| miR-10b-5p | miR-10b-5p was upregulated in PC12 Q73 cells, enhancing cell survival under apoptotic stress. Increased levels were linked to HD pathology, earlier disease onset, and CAG repeat length in postmortem brain tissue. Elevated plasma levels suggest its potential as a biomarker for predicting HD onset and severity, possibly through BDNF regulation. | [88] | |
| Epilepsy | miR-146a-5p | miR-146a-5p was significantly elevated during seizures and in drug-resistant epilepsy patients. Increased levels correlated with seizure frequency and severity, linking them to neuroinflammation and excitability. | [89] |
| miR-132 | miR-132 was significantly upregulated in epilepsy patients (p < 0.01), linking it to neuronal excitability and epilepsy pathophysiology. | [90] | |
| Disorders of consciousness | miR-150-5p | Reduced expression was observed in patients with (p = 0.003) compared to healthy controls at the time of study inclusion. Expression levels returned to normal six months post-injury in TBI patients. | [91] |
AD: Alzheimer’s disease; ALS: amyotrophic lateral sclerosis; CSF: cerebrospinal fluid; ERK1/2: extracellular signal-regulated kinase 1/2; iPSCs: induced pluripotent stem cells; PD: Parkinson’s disease; MCI: mild cognitive impairment; miRNA: microRNA; MSA: multiple system atrophy