Role of Retroelements in Frontotemporal Dementia Development.

Frontotemporal dementia (FTD) develops in proteinopathies involving TDP-43 (transactive response DNA-binding protein 43 kDa), tau, and FUS (fused in sarcoma) proteins, which possess antiviral properties and exert inhibitory effects on human transposable elements. Viruses and aging have been suggested to trigger FTD by activating specific retroelements. FTD is associated with multiple single nucleotide polymorphisms (SNPs), most located in intergenic and regulatory regions where many transposable element genes are found. Therefore, genetic predisposition to FTD may influence the interaction between retroelements and the TDP-43, tau, and FUS proteins, causing pathological conformation changes and aggregate formation. Subsequently, these aggregates lose their ability to inhibit retroelements, leading to the activation of transposable elements. This creates a harmful negative feedback loop in which TDP-43, tau, and FUS protein expressions are further enhanced by retroelement transcripts and proteins, resulting in protein aggregate accumulation and pathological disease progression. Hence, epigenetic inhibition of pathologically activated retroelements using micro-ribonucleic acids (microRNAs) derived from transposable elements has been proposed as a potential treatment for FTD. Finally, a review of the current scientific literature identified 13 appropriate microRNAs (miR-1246, -181c, -330, -345-5p, -361, -548a-3p, -548b-5p, -548c-5p, -571, -588, -659-3p, -708-3p, -887).