Autosomal dominant lateral temporal epilepsy (ADTLE) is a partial epilepsy caused by mutations in LGI1, a multidomain protein of unknown function. To begin to understand the biological function of LGI1, we have determined its pattern of glycosylation, subcellular expression and capacity for secretion. LGI1 is expressed as two different isoforms in the brain, and we show that the long isoform is a secreted protein, whereas the short isoform is retained in an intracellular pool. ADLTE-related mutants of the long form are defective for secretion and are retained in the endoplasmic reticulum and Golgi complex. Finally, we show that normal secreted LGI1 specifically binds to the cell surface of differentiated PC12 cells. We propose that LGI1 is a secreted factor important for neuronal development and that ADTLE is a disease that results from the loss of regulation in the protein available either extracellular or intracellularly.

Remyelination is a key aspect in multiple sclerosis pathology and a special effort is being made to promote it. However, there is still no available treatment to regenerate myelin and several strategies are being scrutinized. Myelination is naturally performed by oligodendrocytes and microRNAs have been postulated as a promising tool to induce oligodendrocyte precursor cell differentiation and therefore remyelination. Herein, DSPC liposomes and PLGA nanoparticles were studied for miR-219a-5p encapsulation, release and remyelination promotion. In parallel, they were compared with biologically engineered extracellular vesicles overexpressing miR-219a-5p. Interestingly, extracellular vesicles showed the highest oligodendrocyte precursor cell differentiation levels and were more effective than liposomes and polymeric nanoparticles crossing the blood–brain barrier. Finally, extracellular vesicles were able to improve EAE animal model clinical evolution. Our results indicate that the use of extracellular vesicles as miR-219a-5p delivery system can be a feasible and promising strategy to induce remyelination in multiple sclerosis patients.

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Porous implants play a crucial role in allowing ingrowth of host connective tissue and thereby help in keeping the implant in its place. With the aim of mimicking the microstructure of natural extracellular matrix, ultrahigh-molecular-weight polyethylene (UHMWPE) porous samples with a desirable pore size distribution were developed by combining thermally induced phase separation and salt leaching techniques. The porous UHMWPE samples consisted of a nanofibrous UHMWPE matrix with a fibre diameter smaller than 500 nm, highly interconnected, with a controllable pore diameter from nanoscale to 300 µm. Moreover, a porous UHMWPE sample was also developed as a continuous and homogeneous coating onto the UHMWPE dense sample. The dense/porous UHMWPE sample supported human foetal osteoblast 1.19 cell line proliferation and differentiation, indicating the potential of porous UHMWPE with a desirable pore size distribution for bone application. An osseointegration model in the sheep revealed substantial bone formation within the pore layer at 12 weeks via SEM evaluation. Ingrown bone was more closely opposed to the pore wall when compared to the dense UHMWPE control. These results indicate that dense/porous UHMWPE could provide improved osseointegration while maintaining the structural integrity necessary for load-bearing orthopaedic application.

Mutations in the LGI1/Epitempin gene cause autosomal dominant lateral temporal lobe epilepsy (ADLTE), a partial epilepsy characterized by the presence of auditory seizures. However, not all the pedigrees with a phenotype consistent with ADLTE show mutations in LGI1/Epitempin, or evidence for linkage to the 10q24 locus. Other authors as well as ourselves have found an internal repeat (EPTP, pfam# PF03736) that allowed the identification of three other genes sharing a sequence and structural similarity with LGI1/Epitempin. In this work, we present the sequencing of these genes in a set of ADLTE families without mutations in both LGI1/Epitempin and sporadic cases. No analyzed polymorphisms modified susceptibility in either the familial or sporadic forms of this partial epilepsy.