Why do you think your paper is highly cited?

I believe it provides important new information that is also somewhat controversial.

 Would you summarize the significance of your paper in layman's terms?

We have demonstrated that an abnormal form of the protein TDP-43 is a consistent finding in all subtypes of amyotrophic lateral sclerosis (ALS), with the exception of those caused by mutations in the superoxide dismutase 1 (SOD1) gene. This absolute biochemical difference suggests that mutant SOD1 may cause motor neurons to die through some different mechanism than occurs in sporadic ALS. This has great implications since SOD1 mutant mice are the most commonly used animal model in ALS research and many of the proposed therapies are targeted towards SOD1-related pathways. Our findings suggest this approach may not be appropriate.

 How did you become involved in this research, and were there any problems along the way?

My main research interest is in the molecular pathology of neurodegenerative diseases, in particular, frontotemporal dementia (FTD). FTD overlaps with ALS, with one of the common features being the presence of abnormal TDP-43 protein. I was part of the research team that originally identified TDP-43 in FTD.

The purpose of the present study was to better characterize TDP-43 pathology in ALS. The only problem in performing the study was accumulating sufficient numbers of cases with SOD1 mutations, which are quite rare. A greater problem has been having the results accepted by the ALS research community, which is slow to admit that the SOD1 model they have used for the past decade may have significant limitations.

 Where do you see your research leading in the future?

The discovery of TDP-43 provides important new insight into the pathogenesis of ALS. The central role of this protein has recently been confirmed with the discovery of mutations in the gene (TARDBP) in cases of familial and sporadic ALS. Already, TDP-43 has become a major focus in ALS research and TARDBP mutant mice will soon become a valuable experimental model.

 Do you foresee any social or political implications for your research?

Hopefully, it will lead to more rapid advances in developing useful treatment strategies for ALS.

Ian R. A. Mackenzie, M.D., FRCPC
Department of Pathology & Laboratory Medicine
Vancouver General Hospital
Vancouver, BC, Canada

Keywords: amyotrophic lateral sclerosis, superoxide dismutase 1, motor neurons, molecular pathology, neurodegenerative diseases, frontotemporal dementia.