Widespread alterations in microRNA biogenesis in human Huntington’s disease putamen

Abstract

Altered microRNA (miRNA) expression is a common feature of Huntington’s disease (HD) and could participate in disease onset and progression. However, little is known about the underlying causes of miRNA disruption in HD. We and others have previously shown that mutant Huntingtin binds to Ago2, a central component of miRNA biogenesis, and disrupts mature miRNA levels. In this study, we sought to determine if miRNA maturation per se was compromised in HD. Towards this end, we characterized major miRNA biogenesis pathway components and miRNA maturation products (pri-miRNA, pre-miRNA, and mature) in human HD (N = 41, Vonsattel grades HD2-4) and healthy control (N = 25) subjects. Notably, the striatum (putamen) and cortex (BA39) from the same individuals were analyzed in parallel. We show that Ago2, Drosha, and Dicer were strongly downregulated in human HD at the early stages of the disease. Using a panel of HD-related miRNAs (miR-10b, miR-196b, miR-132, miR-212, miR-127, miR-128), we uncovered various types of maturation defects in the HD brain, the most prominent occurring at the pre-miRNA to mature miRNA maturation step. Consistent with earlier findings, we provide evidence that alterations in autophagy could participate in miRNA maturation defects. Notably, most changes occurred in the striatum, which is more prone to HTT aggregation and neurodegeneration. Likewise, we observed no significant alterations in miRNA biogenesis in human HD cortex and blood, strengthening tissue-specific effects. Overall, these data provide important clues into the underlying mechanisms behind miRNA alterations in HD-susceptible tissues. Further investigations are now required to understand the biological, diagnostic, and therapeutic implications of miRNA/RNAi biogenesis defects in HD and related neurodegenerative disorders.

A role for astrocytic miR-129-5p in Frontotemporal Dementia

“…Extensive research has focused on miR-212-5p in the adult brain. Reductions in its levels have been associated with memory impairment in mice [34] [35] [36], and miR-212-5p is known to be decreased in several neurodegenerative diseases such as Alzheimer’s disease (AD), Huntington’s disease, and Parkinson’s disease (PD) [37] [38] [39] [40] [41] [42] [43] [44] [45]. Additional studies suggest that targeting miR-212-5p expression is neuroprotective in models of PD, AD, and traumatic brain injury [46] [47] [48].…”

“…Deletion of the miR-132/212 cluster impairs synaptic plasticity and memory consolidation in mice [34] [35] [36], suggesting that the decrease of miR-212-5p likely contributes to FTD pathology. Moreover, miR-212-5p was found decreased in several other neurodegenerative diseases such as AD, Huntington’s disease, and PD [37] [38] [39] [40] [41] [42] [43] [44] [45], indicating a key role in neurodegenerative diseases. Additional studies suggest that targeting miR-212-5p expression is neuroprotective in models of PD, AD, and traumatic brain injury [46] [47] [48].…”

MiR-128-3p – a gray eminence of the human central nervous system

“…The deregulation of miR-128-3p expression in a cell-specific manner is associated with neurological disorders due to its function in different cell types. 47 , 48 , 49 , 50 …”

Mutant huntingtin induces neuronal apoptosis via derepressing the non-canonical poly(A) polymerase PAPD5

“…miRNA dysregulation has been reported in HD disease models 22 and patients. 23,24 Next, we further investigated this PAPD5-miRNA-activated caspase cascade in HD disease models.…”