> Researchers at the University of Pennsylvania School of Medicine have found an absolute biochemical distinction between the sporadic and hereditary variants of Lou Gehrig’s disease, or amyothrophic lateral sclerosis (ALS), suggesting that current approaches to drug discovery should be re-examined.
> By examining the various forms of ALS in post-mortem tissue, the researchers found that TDP-43 was the disease protein in sporadic ALS cases, but not in patients with SOD-1 mutations, all of whom have the familial form of ALS. Patients with the SOD-1 mutation account for about 1 percent of all ALS cases.
> This finding may partially account for why therapeutic strategies, shown to be effective in SOD-1 mouse models, have generally not been effective in clinical trials of sporadic ALS patients.
> The study was published this week in the Annals of Neurology.

(PHILADELPHIA) – Most research on Lou Gehrig’s disease therapeutics has been based on the assumption that its two forms (sporadic and hereditary) are similar in their underlying cause. Now, researchers at the University of Pennsylvania School of Medicine have found an absolute biochemical distinction between these two disease variants, suggesting that current approaches to drug discovery should be re-examined.

TDP-43 ALS Disease Protein

TDP-43 disease protein in amyotrophic lateral sclerosis (ALS) brain tissue

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About 5 percent of all cases of Lou Gehrig’s disease, or amyothrophic lateral sclerosis (ALS), are passed from generation to generation. The most common genetic variant in this familial form is caused by a mutation in the SOD-1 gene. The researchers looked at a large set of ALS patients, including hereditary cases, both with and without the SOD-1 mutation.

The present study – published this week in the Annals of Neurology – was conducted by Penn; a group led by Ian Mackenzie from the University of British Columbia; the University of Munich; and others across the U.S. and Canada.

“Most ALS research has focused on how mutant SOD-1 proteins are toxic to nerve cells,” says senior author John Trojanowski, MD, PhD, who directs the Penn Institute on Aging. Last year, Penn investigators led by co-author Virginia Lee, PhD, who directs the Penn Center for Neurodegenerative Disease Research, identified TDP-43 as the major disease protein in sporadic (non-hereditary) forms of ALS, which are not those caused by SOD-1 gene mutations.

By examining the various forms of ALS in post-mortem tissue, the researchers found that TDP-43 was the disease protein in sporadic ALS cases, but not in patients with SOD-1 mutations, all of whom have the familial form of ALS. Patients with the SOD-1 mutation account for about 1 percent of all ALS cases.

“We argue that SOD-1 ALS does not equal sporadic ALS,” says Trojanowski. “If you pursue drug discovery focusing on SOD-1-mediated pathways of brain and spinal cord degeneration you may benefit SOD-1-bearing patients, but not the vast majority of ALS patients who have the sporadic form of this disorder with TDP-43 pathologies underlying the disease.”

Motor neuron degeneration in TDP-43 cases may result from a different mechanism than cases with SOD-1 mutations, so this form of ALS may not be the familial counterpart of sporadic ALS,” surmises Lee.

“This may also partially account for why therapeutic strategies, shown to be effective in SOD-1 mouse models, have generally not been effective in clinical trials of sporadic ALS patients,” explains Trojanowski. “This also sounds a cautionary note in all other diseases in which you have familial and sporadic versions of the disease because it will prompt researchers to ask if mouse models for drug discovery are based on the correct mutations or disease protein.”

This research was funded by the Canadian Institutes of Health Research, the National Institute on Aging, the German Federal Ministry of Education and Research, The Wellcome Trust (United Kingdom) and the UK Medical Research Council.

Co-authors in addition to Trojanowski, Lee, and Mackenzie are Eileen H. Bigio, Paul G. Ince, Felix Geser, Manuela Neumann, Nigel J. Cairns, Linda K. Kwong, Mark S. Forman, John Ravits, Heather Stewart, Andrew Eisen, Leo McClusky, Hans A. Kretzschmar, Camelia M. Monoranu, J. Robin Highley, Janine Kirby, Teepu Siddique, and Pamela J. Shaw.

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The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year.

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