Pathogenic Mechanisms in Amyotrophic Lateral Sclerosis

Dr. Nguyen received his PhD at the Centre for Neuroscience at McGill University where he studied the pathogenesis of amyotrophic lateral sclerosis (ALS), the most common form of human motor neuron disease. He made several important contributions to the field:

 

- His research elucidated the contribution of cytoskeletal proteins and particularly that of neuronal intermediate filaments (NFs) in ALS. Large spinal motor neurons have large axon caliber filled densely with NFs. Because these neurons selectively die in ALS and NFs aggregation is a central feature of the disease, it has been thought for a long time that the burden of NFs in these axons predisposes them to motor neuron death. By generating a compound mutant mouse model bearing a mutant superoxide dismutase 1-linked to familial ALS with a 50% reduction in NF content and in axon caliber. Dr. Nguyen found out that these large spinal motor neurons with reduced axonal caliber still die at the same rate. Thus, the large axonal caliber is not a determinant factor in selective vulnerability (Nguyen al., PNAS 1998). Further, he found out that large accumulations of NFs in motor neuron cell body are not detrimental but rather neuroprotective against mutant SOD1-induced toxicity (Nguyen et al., Neuron 2001).

 

- Dr. Nguyen and his colleagues also found that toxicity induced by mutant superoxide dismutase 1-linked to familial ALS is non-cell autonomous i.e. the disease can spread from a mutant neuron to a non-mutant neuron through inflammatory processes (Clement et al., Science 2003). He also developed a rationale for targeting the innate immunity and inflammation to block ALS progression (Nguyen et al., Annals of Neurology 2001, Nature Review Neuroscience 2002, J Neuroscience 2004; Kriz et al., Neurobiology of Disease 2002; Clement et al., Science 2003).

 

Why are these studies important? They went against old dogma in the field and set the stage for our current understanding of the molecular basis of selective vulnerability in neurodegeneration. The body of work also identified new targets and therapies for the treatment of neurodegeneration and most importantly, has directly impacted human health since these findings and concepts are currently being tested, applied and extrapolated to other neurodegenerative disorders.