Age-Related microRNA Overexpression in Lafora Disease Male Mice Provides Links between Neuroinflammation and Oxidative Stress

Abstract

Lafora disease is a rare, fatal form of progressive myoclonus epilepsy characterized by continuous neurodegeneration with epileptic seizures, characterized by the intracellular accumulation of aberrant polyglucosan granules called Lafora bodies. Several works have provided numerous evidence of molecular and cellular alterations in neural tissue from experimental mouse models deficient in either laforin or malin, two proteins related to the disease. Oxidative stress, alterations in proteostasis, and deregulation of inflammatory signals are some of the molecular alterations underlying this condition in both KO animal models. Lafora bodies appear early in the animal’s life, but many of the aforementioned molecular aberrant processes and the consequent neurological symptoms ensue only as animals age. Here, using small RNA-seq and quantitative PCR on brain extracts from laforin and malin KO male mice of different ages, we show that two different microRNA species, miR-155 and miR-146a, are overexpressed in an age-dependent manner. We also observed altered expression of putative target genes for each of the microRNAs studied in brain extracts. These results open the path for a detailed dissection of the molecular consequences of laforin and malin deficiency in brain tissue, as well as the potential role of miR-155 and miR-146a as specific biomarkers of disease progression in LD.

Exploring miRNA–target gene pair detection in disease with coRmiT

“…Both miR-155 and miR-146a have been shown to be involved in complementary regulatory pathways activated during the inflammatory response, being the first pro-inflammatory and the second anti-inflammatory [ 53 ]. We showed that both miRNAs are overexpressed, in an age-dependent manner in brains from Epm2a-/- and Epm2b-/- mice models [ 30 ]. Interestingly, this overexpression coincided with the increased expression of putative target genes involved in the inflammatory cascade and oxidative stress responses, such as Sod2 , Socs1 and Traf6 [ 30 ].…”

“…We showed that both miRNAs are overexpressed, in an age-dependent manner in brains from Epm2a-/- and Epm2b-/- mice models [ 30 ]. Interestingly, this overexpression coincided with the increased expression of putative target genes involved in the inflammatory cascade and oxidative stress responses, such as Sod2 , Socs1 and Traf6 [ 30 ]. The joint action of both miRNAs has also been detected in systemic lupus erythematosus (SLE) patients [ 54 ].…”

“…The average depth was 18.0 M reads for the RNA-Seq samples and 5.6 M reads for the smallRNA-Seq samples. Further sequencing details for the RNA-Seq experiment are given in [ 28 , 29 ] (mRNA) and [ 30 ] (miRNA).…”