Abstracts

We have identified two genes associated to Lafora disease.In our null mutant mice (EPM2A), we have studied the immunocytochemical architecture of the neurocytoskeleton and the Lafora bodies ., Our Laforin-deficient knockout mice were produced by deleting the Laforin domain coding region of the EPM2A gene (Hum Mol Genet 11:1252-1262.2002). Similar groups of control and homozygous null mutant mice were sacrificed at fixed intervals and their encephalons were fixed with glutaraldehyhde and processed with PAS and immunocytochemical techniques. Monoclonal antibodies were used against neurofilaments M and L (NFM/L) ., Our experimental animals showed neuronal death at 2 months of age, in the absence of apoptotic changes or accumulation of Lafora bodies (LfB). At 9 months of age the number of LfB was very prominent in large nerve cells . They were positive to PAS, Ubiquitin and AGEP. Large neurons from the brainstem, hippocampus and cerebellum showed abnormal immunoreaction for NFM/L , which, in some cases, very much resembled neurofibrillary degeneration. Clusters of fragmented and distorted neurites were seen , very much like [quot]senile[quot] (neurite) plaques. Analysis of LfB has revealed some unexpected structural components that appear to establish an anatomofunctional link between them and the neurocytoskeleton ., Our observations apppear to indicate that our model of Lafora disease presents morphological evidence of a neurodegenerative process in absence of apoptotic cell death . Lafora bodies do not primarily participate in neuronal death . With age, they increase in size and number , accumulating poliglucosans and, probably, also misfolded proteins. The presence of a complex structure in the ring of Lafora bodies, allows us to postulate an active role for these still enigmatic inclusions., (Supported by NINDS 5RO1NS042376-03.)