Findings on seizure susceptibility open new avenues to understanding epilepsy in rapid progressive dementia

Image: Hippocampal section of two prion protein knock-out mice that over-express a truncated form of the prion protein DF35. On the left, a Nissl staining of a non-treated mice showing the typical structure of the CA1-CA3 pyramidal layers. On the right, FluoroJade B staining 24h after the KA-treatment. The stain specifically marks neuronal degeneration, so the neurodegenerative pattern shown is related only to KA-treatment, demonstrating the essential neuroprotective role of the prion protein.

PrPC – found naturally in healthy brain and decreased in several diseases such us diseases such as bovine spongiform encephalopathy (BSE) and human rapid progressive dementia (RPD) CJD – has long been thought to be neuroprotective, so the IBEC researchers hypothesized that an explanation for seizure symptoms in these neurodegenerative diseases could be associated with the loss of function of PrPC.

“We performed a comparative analysis of seizure susceptibility using mice with six different genetic backgrounds and several in vitro experiments,” says José Antonio del Río, who leads the Molecular and Cellular Neurobiotechnology group at IBEC. “We indeed demonstrated that mice lacking PrPC showed an increased susceptibility to epileptic episodes leading to cell death in the hippocampal region, supporting the notion that the protein is involved in neuroprotection against seizures, and that it actively participates in the increased epileptic response observed in mice, independently of the genetic background, that lack it.”

Their study, which also involved researchers at the UB, IDIBELL, CIBERNED, CISA-INIA, DZNE in Germany, and SISSA in Italy, also revealed that other factors in parallel with PrPC deletion, such as the genetic background of some of the mice used for PrPC analysis, or the presence of so-called ‘Prnp-flanking genes’ in the mixed genetic background of PrPC knockout mice, might contribute to susceptibility to epileptic fits in the absence of PrPC.

“In the neurodegeneration found in rapid progressive dementia cases of CJD, Alzheimer’s or Dementia with Lewy Bodies, the survival time from clinical diagnosis to death is very short, with tremor and epileptic seizures being a common and clinical feature for some of these dementias,” says del Río. “With our new findings, we’re a step closer to understanding more about the neurodegenerative diseases that involve epileptic seizures, which means a step closer to developing new therapies or diagnostic tools.”

Reference: Patricia Carulla, Franc Llorens, Andreu Matamoros-Angles, Patricia Aguilar-Calvo, Juan Carlos Espinosa, Rosalina Gavín, Isidre Ferrer, Giuseppe Legname, Juan Maria Torres & José A. del Río (2015). Involvement of PrPC in kainate-induced excitotoxicity in several mouse strains. Scientific Reports, 5, 11971

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