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Most ALS May Stem from Protein Misfolding

By Crystal Phend, Senior Staff Writer, MedPage Today


Published: October 17, 2010


Reviewed by

Adam J. Carinci, MD; Instructor, Harvard Medical School and

Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner



Amyotrophic lateral sclerosis (ALS) may be a disease of protein misfolding, according to a study that affirms that abnormal protein structure found in inherited cases plays a role in sporadic cases as well.


Shape change in the superoxide dismutase 1 (SOD1) protein may be the common source of motor neuron death behind most ALS, Robert H. Brown, Jr., MD, DPhil, of the University of Massachusetts Medical Center in Worcester, Mass., and colleagues reported online in Nature Neuroscience.


Their protein analysis of SOD1 from ALS patients showed the same specific conformational change in mutated SOD1 and wild-type protein that had been damaged by oxidation in roughly half of the sporadic cases.


Action Points

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Explain to interested patients that data from a recent study indicates that amyotrophic lateral sclerosis is likely a result of protein misfolding in both inherited and sporadic cases.




Note that data from this study need further analysis and confirmation before definitive conclusions can be drawn.


"These results indicate that at least a subset of sporadic ALS cases contain wild-type SOD1 proteins that are structurally similar to familial ALS-linked SOD1 mutant proteins," Brown's group wrote in the paper.


If the results are confirmed, findings from mouse models of inherited ALS -- easier to model than sporadic ALS -- could be used to develop treatments that would benefit the majority of ALS patients, according to a press release.


The findings are exciting, agreed Jeffrey Rothstein, MD, PhD, director of the Center for ALS Research at Johns Hopkins, who was not involved in the study.


A clinical trial is underway to determine if turning off SOD1 with an antisense drug would work in familial cases carrying the mutated form of the protein, he noted.


If it works, the common pathway suggests sporadic cases could benefit too, he told MedPage Today.


Familial ALS, thought to result in most cases from SOD1 mutation, account for no more than 10% of ALS cases.


The cause of the vast majority of ALS cases, termed sporadic, has been largely unknown.


However, another potentially competing common pathway -- the protein TDP43 -- has also recently been discovered for sporadic and familial ALS, Rothstein noted.


"We have these two conflicting, ongoing hypotheses about a mutant protein and a rare familial subset being relevant to the more common sporadic disease," he said in an interview. "Who's right? I don't know, but that's how we move forward."


The researchers used a newly developed monoclonal antibody that can distinguish between misfolded proteins of mutated SOD1 and normal SOD1.


When they tested this agent known as C4F6 on protein samples, they found that oxidized SOD1 proteins generated the same response as the mutated form whereas the normal, unoxidized protein did not.


In the body, this type of oxidation typically arises during cellular stress, making it a potential cause of sporadic ALS.


Denaturing the proteins to strip away any shape differences eliminated the effect, indicating that a conformational change induced by oxidation was responsible for the similarity to the mutated form.


Immunochemical analysis confirmed that the faulty protein conformation was the same for the mutated and oxidized forms and appeared to be preventing transport of molecules down the axon of the motor neuron, which is thought to result in motor neuron degeneration and die off.


The researchers then checked for reactions to the monoclonal antibody in spinal cord tissue samples from deceased patients who had sporadic ALS, which would confirm in vivo similarity to mutant SOD1.


Four of the nine sporadic cases did stain positive with the monoclonal antibody, suggesting presence of the oxidized SOD1.


Two of the other five cases showed such extensive motor degeneration that no motor neurons to stain could be detected.


None of the 17 control cases without ALS stained positive.


Thus, immunohistochemistry suggested that misfolded wild-type SOD1 was significantly associated with many sporadic ALS cases (P<0.05), Brown's group wrote.


They noted that there is a precedent for the idea that proteins can cause neurodegenerative disease via both inheritable and non-inheritable modifications as seen with alpha-synuclein in Parkinson's disease and beta-amyloid and tau proteins in Alzheimer's disease and frontotemporal dementia.


The researchers cautioned that they couldn't rule out other misfolded forms of SOD1 that might not have been picked up by the monoclonal antibody but still lead to the same "structural consequences."


Rothstein also warned that the study used only a small number of human samples and did not test for toxic consequences in the human tissue, only other types of samples.


The study was supported by the ALS Therapy Alliance-CVS Pharmacy, 2007/2008 Marine Biological Laboratory research fellowships, the ALS Association, the U.S. National Institutes of Health, Canadian Institutes of Health Research, the Angel Fund, and Project ALS.


The researchers reported having no conflicts of interest to disclose.


Rothstein reported having no conflicts of interest to disclose.



Primary source: Nature Neuroscience


Source reference:


Bosco DA, et al "Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS" Nat Neurosci 2010; DOI: 10.1038/nn.2660.



© 2004-2010 MedPage Today, LLC. All Rights Reserved.


Medical News: Most ALS May Stem from Protein Misfolding - in Neurology, General Neurology from MedPage Today
 
Very interesting, thank you.
 
very good thanks
 
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