Using a technique that illuminates subtle changes in individual proteins, chemistry researchers at Cornell and Scripps Research Institute have uncovered new insight into the underlying causes of Amyotrophic Lateral Sclerosis (ALS).
The first study, which proved the principle of imaging protein structures via pulsed dipolar electron spin resonance (ESR) spectroscopy, was published in Biophysical Journal; the second paper, which used the technique to connect ALS symptoms with protein aggregation, appeared in Proceedings of the National Academy of Sciences (PNAS).
A complex neurodegenerative disease, ALS often has a genetic component, genetic defects that cause it can be inherited. Scientists have long known that one of the culprit genes codes for the protein superoxide dismutase 1 or SOD1, a critical copper-containing enzyme that protects cells against oxidative damage by destroying free radicals.
Scientists have surmised that ALS is a disease related to oxidative damage of neurons, and that might still be true state the team. But the group say that they have provided strong evidence for another hypothesis: that SOD1 mutations cause ALS by destabilizing the SOD1 protein structure. This leads to increased motion of the proteins. This movement was observed promoting their aggregation, or clumping together, an event toxic to the healthy cell.
ALS, in this form, appears to be a protein aggregation disease, much like Alzheimer’s and Parkinson’s diseases.
For a long time, people have studied mutations in SOD1 to try to understand ALS, but the properties of normal proteins and mutated ones were found to be very similar. By using ESR spectroscopy, the scientists for the first time have seen definitive differences. By verifying with other methods, the researchers showed that the dynamics of the proteins were dramatically changed by mutation, and that they showed a tendency to aggregate.
In the PNAS paper, X-ray scattering was also used to study structural changes and the ability of the proteins to interact with each other. The researchers found that levels of protein aggregation correlated with the severity of ALS symptoms.
Their conclusions point to the possibility of ALS being more linked to toxicity of aggregation and perhaps less about the effect of the mutations on SOD1 activity. ALS is a late-onset disease, with people being affected in mid to late life. Sporadic mutations in SOD1 arise from natural processes, but it’s not really clear if they’re actually going to generate the disease or not.
The new ESR might be a good diagnostic tool to identify harmful mutations early before symptoms become evident. These methods could also aid in the development of drugs that would bind to and stabilize the proteins to prevent detrimental effects in the first place.
Source: The Cornell Chronicle
Michelle Petersen is the founder of Healthinnovations, having worked in the health and science industry for over 21 years, which includes tenure within the NHS and Oxford University. Healthinnovations is a publication that has reported on, influenced, and researched current and future innovations in health for the past decade.
Michelle has been picked up as an expert writer for Informa publisher’s Clinical Trials community, as well as being listed as a blog source by the world’s leading medical journals, including the acclaimed Nature-Springer journal series.
Healthinnovations is currently indexed by the trusted Altmetric and PlumX metrics systems, respectively, as a blog source for published research globally. Healthinnovations is also featured in the world-renowned BioPortfolio, BioPortfolio.com, the life science, pharmaceutical and healthcare portal.
Most recently the Texas A&M University covered The Top 10 Healthinnovations series on their site with distinguished Professor Stephen Maren calling the inclusion of himself and his team on the list a reflection of “the hard work and dedication of my students and trainees”.
Michelle Petersen’s copy was used in the highly successful marketing campaign for the mega-hit film ‘Jumanji: The Next Level, starring Jack Black, Karen Gilian, Kevin Hart and Dwayne ‘The Rock’ Johnson. Michelle Petersen’s copywriting was part of the film’s coverage by the Republic TV network. Republic TV is the most-watched English language TV channel in India since its inception in 2017.
An avid campaigner in the fight against child sex abuse and trafficking, Michelle is a passionate humanist striving for a better quality of life for all humans by helping to provide traction for new technologies and techniques within healthcare.