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.
