A Clearer Picture of Cloudy Eyes
A new study provides more insight into cataracts, the leading cause of vision loss and blindness in the elderly, finding that small pieces of a perfectly normal protein become toxic during the aging process.
A cataract results from deterioration in the highly ordered assembly of crystallin proteins in the eye lens. Normally, the ordered structure keeps lenses clear and able to efficiently transmit light. However, crystallins gradually break down during aging, causing the lens to become opaque and scatter light instead. Besides age, other risk factors such as diabetes, ultraviolet radiation, or drugs like corticosteroids can also contribute to cataracts.
Like cataracts themselves, the exact mechanisms governing their formation are cloudy, but Krishna Sharma and colleagues found that tiny bits of crystallin greatly contribute to this process.
They compared a range of human donor lenses and found that aged and cataract lenses accumulated about four times as many short (~10-20 amino acids) crystallin fragments compared to young lenses. These fragments could readily bind full-length crystallins, which disrupted their natural shape and organization and caused them to become insoluble.
Ironically, these tiny fragments are a by-product of the eye's efforts to stay healthy; when a crystallin becomes damaged, other proteins chew it up to remove it; but occasionally the process is incomplete, leaving tiny pieces that can cause greater damage.
Corresponding Author: K. Krishna Sharma, Department of Ophthalmology, University of Missouri School of Medicine, Columbia, MO; Phone: 573-882-8478, email: Sharmak@health.missouri.edu
ALS Aggregates are composed of only one protein
Researchers have provided a big new clue to help combat amyotrophic lateral sclerosis (ALS), deciphering that the dense protein aggregates that contribute to the nerve decay of ALS are composed of just one protein: superoxide dismutase (SOD1).
While the aggregation of mutated SOD1, a protein that normally protects cells from free radical damage, is a tell-tale sign of familial ALS, the exact composition of these aggregates has been unclear. Identifying the other proteins present and if they are modified in some way could help answer how they form and why they are so toxic.
Julian Whitelegge and colleagues Joan S. Valentine and David Borchelt used mass spectrometry to uncover the components of these aggregates and discovered, somewhat surprisingly, that they were composed almost entirely of SOD1 (some samples contained trace amounts of random abundant nerve proteins that likely got there by happenstance).
In addition, their analysis of ALS mouse spinal cords showed almost all the SOD1 was fully intact protein and not partial or damaged fragments. Likewise, the researchers did not find evidence for extensive chemical modifications (that were not readily removed by DTT treatment).
While many questions about these aggregates still remain, this study has given scientists a starting point, suggesting that aggregation is an intrinsic property of mutant SOD1, very much like the amyloid plaques associated with Alzheimer's.
Corresponding Author: Julian Whitelegge, The NPI-Semel Institute, David Geffen School of Medicine, UCLA; Phone: 310-794-5156; email: email@example.com
The American Society for Biochemistry and Molecular Biology is a nonprofit scientific and educational organization with over 11,900 members in the United States and internationally. Most members teach and conduct research at colleges and universities. Others conduct research in various government laboratories, nonprofit research institutions and industry. The Society's student members attend undergraduate or graduate institutions.
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