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SCIENTIFIC HIGHLIGHTS from the 13th international symposium on MND

New evidence was provided that degeneration of motor neurons, either associated with toxicity of mutant SOD1 or other toxic factors, i.e. peripherin over expression, is not cellautonomous, that is, it does not derive from toxic action exclusively within motor neurons. The activated glial cells surrounding the motor neurons play an important role in ALS, suggested Dr Robertson of the McGill University of Montreal. She showed that microglia, when activated, secreted inflammatory cytokines that induced an over expression of peripherin splice variant (Per61) leading to the formation of perikaryal and axonal aggregates in the motor neurons. Dr. Ferri of the University of Rome raised a similar issue showing that glioblastoma cell line transfected with mutant SOD1 induced apoptotic death of co-coltured neuroblastoma cells throughout the activation of inflammatory factors. In three separate presentations, Dr. Robertson, Dr. Robberecht of the University of Leuven and Dr. Bendotti of the Mario Negri Institute in Milan, suggested that activation of the intracellular kinase, p38 MAPK, plays a key role in the reactivity of glial cells and their cross-talk with motor neurons in MND. This was supported by the fact that minocycline, which slowed disease progression in two strains of SOD1 mutant mice, was also able to inhibit the activation of p38MAPK, particularly in glial cells (Dr. Robertson, Dr. Robberecht). Neurofilamentous aggregates in motor neurons represent a pathological hallmark of ALS but it is still unclear how the toxicity in the cell develops. Dr. Strong and Dr. Sanelli from Robarts Research Institute of London, Ontario, using in vitro cultured motor neurons demonstrated that neurofilament aggregates may increase the susceptibility of these cells to excitotoxicity by deregulating calcium influx induced by stimulation of NMDA glutamate receptor. Nine years following the discovery that mutations in SOD1 cause ALS in human and a similar disease in transgenic rodents, some light was shed upon the mechanism of toxicity of this mutant enzyme. Dr Marklund from Umea University of Sweden, Dr. Turner from Monash University of Victoria and Dr. Cashman from the University of Toronto, in separate presentations, strengthened the hypothesis that the burden of intracellular SOD1 aggregates, either due to the misfolding of protein, proteasome inhibition, and/or isomorphic recruitment of SOD1, may be the cause of motor neuron degeneration in this form of familial ALS. Dr. Goldstein from University of Kuopio, Finland, suggested that strong oxidation of the mutant SOD1 is likely the cause of conformational changes in this protein that lead to its aggregation. Two different molecular strategies to inhibit the production of SOD1 mutants were proposed by Dr Smith of the Centre for Neurological Study of California and Dr. Xu of the University of Massachussets Medical School. Dr. Smith evaluated the ability of different antisense DNA oligonucleotides to down regulate the expression of SOD1 mRNA in human cell lines. He then showed that oligonucleotides are taken up by spinal motor neurons after intracerebroventricular injection in transgenic SOD1 mutant rats although experiments are still underway to demonstrate the neuroprotective effect on these cells. Dr. Xu, using the tools adopted normally by the cells to eliminate defective messenger RNAs, i.e. RNA silencing by small interfering RNAs sequences (siRNAs), was able to selectively suppress the expression of mutant SOD1 but not wild type SOD1 in either in vitro or in vivo experimental models. These nucleic acid based treatments, if proved effective in halting the progression of the disease in SOD1 mutants model, may encourage gene therapy in familial ALS.