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Cornell scientists show that ALS is a protein aggregation disease.

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

 

Distances from key SOD structural elements to G93. (A) Stereo view image of G93 and the active site of one SOD subunit. The exposed G93 loop is connected to the active site metals (labeled spheres) through predictably stabilizing, dense-packing interactions (mesh) along∼19- and∼24-Å paths that transverse the β-barrel. This loop caps the β-barrel opposite the metals. (B) The copper site within Cu, Zn SOD is tied energetically into the β-barrel fold. All four copper histidine ligands are linked to key structural elements of the SOD framework. H46 resides adjacent to hydrophobic core residues F45, L117, and I18 (gray mesh). H48 resides near the disulfide formed between C57 and C146 (sea green). H63 forms part of the compact zinc loop (black). H120 links the electrostatic loop (yellow) to internal packing of the β-strands (two flanking strands shown in beige).  Aggregation propensities of superoxide dismutase G93 hotspot mutants mirror ALS clinical phenotypes.  Getzoff et al 2014.
Distances from key SOD structural elements to G93. (A) Stereo view image of G93 and the active site of one SOD subunit. The exposed G93 loop is connected to the active site metals (labeled spheres) through predictably stabilizing, dense-packing interactions (mesh) along∼19- and∼24-Å paths that transverse the β-barrel. This loop caps the β-barrel opposite the metals. (B) The copper site within Cu, Zn SOD is tied energetically into the β-barrel fold. All four copper histidine ligands are linked to key structural elements of the SOD framework. H46 resides adjacent to hydrophobic core residues F45, L117, and I18 (gray mesh). H48 resides near the disulfide formed between C57 and C146 (sea green). H63 forms part of the compact zinc loop (black). H120 links the electrostatic loop (yellow) to internal packing of the β-strands (two flanking strands shown in beige). Aggregation propensities of superoxide dismutase G93 hotspot mutants mirror ALS clinical phenotypes. Getzoff et al 2014.

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