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Biological Chemistry

Finding a role for polyglutamine in neurodegenerative diseases

Repeating amino acid sequence seen in disease-related proteins may regulate cellular garbage disposals

by Michael Torrice
June 27, 2017 | A version of this story appeared in Volume 95, Issue 18

In nine neurodegenerative diseases, the culprit is an increase in the number of repeated glutamines in a certain protein. For example, healthy people have between six and 35 glutamines in a row in their huntingtin proteins, whereas people with Huntington’s disease can have more than 100.

With these expanded polyglutamine (polyQ) tracts, the proteins tend to aggregate, but scientists don’t know how the mutant proteins cause neurodegeneration when they’re instead floating freely around cells.

Now a team of researchers reports that the nonexpanded polyQ tract of one protein helps regulate how cells dispose of their molecular garbage. The findings also suggest that expanded tracts associated with disease might disrupt that disposal process (Nature 2017, DOI: 10.1038/nature22078).

Cells trigger a process called autophagy to clear out aggregated proteins, lipids, and other—possibly toxic—junk in their cytoplasm. David C. Rubinsztein of the University of Cambridge and colleagues found that when they decreased expression of a protein called ataxin-3 in cells, autophagy slowed.

Ataxin-3 has a polyQ tract, and expansion of it leads to the neurodegenerative disease spinocerebellar ataxia type 3. Rubinsztein’s team found that normal ataxin-3 keeps autophagy running smoothly by protecting a key autophagy protein called beclin-1 from degradation. To do this, ataxin-3’s polyQ tract first binds to beclin-1.

The scientists determined that longer polyQ tracts—such as those in disease versions of huntingtin—bind beclin-1 more strongly, outcompeting normal ataxin-3. As a result, beclin-1 levels drop and autophagy slows in the cells. When studying cells derived from patients with Huntington’s disease, the scientists found that rates of autophagy were also decreased.


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