Role of miRNAs in Frontotemporal Dementia and Related Disorders

Micro RNAs (miRNAs) are a recently identified class of small non-coding RNA molecules with an important function in the regulation of gene expression. By binding to complementary sequences in target mRNAs they suppress the translation of the mRNA by sequestration or degradation of the message. Several miRNAs are specifically expressed or enriched in brain, and some have been associated with neuronal differentiation, synaptic plasticity and memory formation. Recent studies identified specific miRNAs that regulate the expression of genes involved in the pathogenesis of Alzheimer's disease (AD) and Parkinson's disease (PD), suggesting that miRNAs may be a contributing factor in neurodegeneration. Our working hypothesis is miRNA dysregulation contributes to the development and presentation of frontotemporal lobar degeneration (FTLD) and related disorders, including corticobasal degeneration (CBD).

Our current projects include:

  1. miRNA expression profiling of brain tissue of all FTLD pathological subtypes including patients with TDP-43 type 1, 2, and 3 pathology as well as patients with 3R tau (Pick's disease) and 4R tau (CBD) pathology
  2. miRNA expression profiling of GRN mutation carriers
  3. Identification of miRNAs that regulate total tau expression or that perturb the 3R/4R tau isoforms ratio in-vitro using luciferase reporter assays

The identification of a set of specific miRNAs and their target mRNAs that are implicated in FTLD pathogenesis is expected to broaden our biological understanding of FTLD and its disease pathways. In addition, it could drive a new field of research aimed at the study of miRNAs as potential therapeutic targets for FTLD as well as related tauopathies and TDP43-proteinopathies.