Frontotemporal lobar degeneration (FTLD) is the second most common cause of early-onset dementia after Alzheimer's Disease (AD) . FTLD patients are clinically characterized by personality changes and disinhibited behaviour, often combined with a gradual and progressive language dysfunction . Memory impairment is typically preserved in the early phase of disease, which distinguishes them from patients with AD. Pathologically, around 40% of FTLD patients present with neuronal and/or glial tau aggregates (FTLD-tau), whereas the majority of FTLD patients show ubiquitin-immunoreactive cytoplasmic and intranuclear inclusions historically referred to as FTLD-U (FTLD with ubiquitin-positive inclusions) . More recently, it was shown that hyperphosphorylated and C-terminal truncated fragments of the nuclear protein TAR DNA-binding protein 43 (TDP-43) were the main component of the pathological inclusions in FTLD-U, and the term FTLD-TDP was introduced [4, 5]. Three main patterns of TDP-43 pathology are recognized in FTLD-TDP, based on the anatomical distribution, morphology, and relative proportion of distinct types of inclusions [6, 7]. In this study, we will follow the nomenclature based on the Mackenzie scheme  where FTLD-TDP type 1 is characterized by TDP-43 positive compact neuronal cytoplasmic inclusions and short neurites, FTLD-TDP type 2 presents with long TDP-43 positive neurites and FTLD-TDP type 3 is characterized by compact and granular cytoplasmic inclusions.
In the past decade, several different genes and chromosomal loci have been associated with FTLD. Mutations in the microtubule associated protein tau (MAPT) gene were first identified as a cause of familial FTLD-tau [8–10]. More recently, our group and others discovered that heterozygous mutations in the progranulin gene (PGRN) cause FTLD-TDP through a loss of function mechanism [11, 12]. Patients with PGRN mutations maintain only a single functional copy of the gene, leading to the loss of 50% of functional PGRN, causing disease through haploinsufficiency. The reduced level of PGRN, a growth factor with a key role in a variety of cellular responses, provokes neurodegeneration and associated symptomatology in FTLD patients, including deficits in behaviour, language, and movement [13–15]. Interestingly, all patients with PGRN mutations present with FTLD-TDP pathology type 1 [16, 17]; however, FTLD-TDP Type 1 is also observed in a subset of FTLD-TDP patients without PGRN mutations. Although there are clear pathologic distinctions in FTLD-TDP, the molecular pathways which underlie its progression are still mostly undefined. Recent advances in our understanding of the mammalian genomes, however, have revealed novel regulatory mechanisms with critical roles in disease pathogenesis, thus offering new avenues to explore.
The recent discovery of pervasive expression for noncoding RNAs (ncRNAs) in our genomes through extensive 'transcriptomic' efforts [18–23] has significantly enhanced our fundamental knowledge of cellular signaling cascades and will likely reshape future drug discovery efforts. Indeed, PGRN mutation carriers diagnosed with FTLD exhibit a range of pathologic and phenotypic outcomes, suggesting that other contributing factors, such as ncRNAs, mediate disease progression [4, 11, 12, 15, 19, 24].
The miRNA class of ncRNA, in particular, has generated a lot of interest as their widespread role in many cellular functions becomes increasingly apparent [18, 25–31]. One miRNA can control the expression of hundreds of downstream gene targets, underscoring the importance of characterizing their functional roles in vitro and in vivo . Over the last few years, a growing number of publications have reported dysregulation of miRNA expression in numerous diseases, including neurodegenerative disorders, such as Alzheimer's disease and Huntington's disease [28, 32–34]. Recent reports have also examined miRNA regulation of PGRN, suggesting that this gene is under the control of ncRNAs, including miR-107, and miR-29b [35, 36]. Furthermore, our group previously showed a functional disruption of a miR-659 binding site in FTLD patients with a common genetic variant of PGRN (rs5848) .
Here we profiled miRNA expression in the frontal cortex of a population of FTLD-TDP patients with PGRN mutations and compared their miRNA expression pattern with a large group of FTLD-TDP patients without PGRN mutations, with the goal to identify miRNAs responsive to PGRN haploinsufficiency. For those miRNAs showing greatest evidence of dysregulation and that were validated technically by quantitative real-time PCR in frontal cortex, we further examined their expression in the cerebellum, with the expectation that PGRN levels are globally disrupted throughout the CNS. Finally, we developed a unique list of gene targets predicted to be regulated by miRNAs dysregulated in both frontal cortex and cerebellum in our patient samples, based on previously reported microarray mRNA data as well as bioinformatic miRNA target prediction sites.