May 25, 2007

Does TDP-43 Separate
One Form of ALS From Others?

Amyotrophic lateral sclerosis (ALS) that stems from any of a number of mutations in the SOD1 gene may be biochemically different from ALS from other causes, suggests a report published in the May issue of Annals of Neurology. SOD1-related ALS accounts for 1 percent to 3 percent of all ALS cases.

Ian Mackenzie at the University of British Columbia in Vancouver, with colleagues in Canada, the United States and the United Kingdom, found that the presence of a protein called TDP-43 in the nervous system distinguishes non-SOD1 ALS from SOD1 ALS.

The researchers studied postmortem tissue from 59 people with sporadic (nonfamilial) ALS, 15 people with ALS and SOD1 gene mutations, 11 with familial ALS but without SOD1 gene mutations, and 26 people who had ALS with severe cognitive impairment (dementia). Sporadic ALS is by far the most common form of the disease, accounting for about 90 percent of cases.

All the samples from people with sporadic ALS, ALS with dementia, and non-SOD1 familial ALS had clusters containing TDP-43 in their nerve cells (neurons) and supporting nervous system cells.

In the clusters, TDP-43 was attached to ubiquitin, which is a protein that tags an abnormal molecule and sends it to the cell’s disposal system.

Samples from those with SOD1-related familial ALS contained clusters, but there was no TDP-43 in them.

“In summary, our data have significant implications for elucidating pathogenic mechanisms(s) in ALS,” the investigators write. They say their “most striking finding is the absence of pathological TDP-43 in any of our cases with SOD1 mutations. The significance of this result is the implication that the pathological processes underlying motor neuron degeneration in SALS [sporadic ALS] are different from those associated with SOD1 mutations.”

However, Jeffrey Rothstein, who directs the MDA/ALS Center at Johns Hopkins University in Baltimore, offers some caveats.

Writing in the same issue of Annals of Neurology, Rothstein says the SOD1 ALS cases included in this study were mostly caused by a mutation that leads to a very rapidly fatal disease process. He poses the question of whether the other ALS cases might have been more slowly progressive and therefore allowed time for the TDP-43-containing clusters to appear.

He says it’s too soon to draw the conclusion that SOD1 ALS (and therefore rodents with SOD1 ALS) are fundamentally different from other ALS forms.

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