Ian Mackenzie talks with
ScienceWatch.com and answers a few questions about
this month's New Hot Paper in the field of Neuroscience
Article Title: Pathological TDP-43 distinguishes
sporadic amyotrophic lateral sclerosis from amyotrophic
lateral sclerosis with SOD1 mutations
IRA, et al.
Journal: ANN NEUROL
Year: MAY 2007
* Vancouver Gen Hosp, Dept Pathol, 855 W 12Th Ave,
Vancouver, BC V5Z 1M9, Canada.
(addresses have been truncated)
Why do you think your paper is highly
I believe it provides important new information that is also somewhat
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?
"The purpose of the present study
was to better characterize TDP-43 pathology
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
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
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