Author response: TRiC’s tricks inhibit huntingtin aggregation
Year: 2013
Type: peer-review
Abstract: Huntington’s disease is an inheritable neurodegenerative disorder that typically begins in mid-adulthood. It initially affects muscle coordination and progresses to include psychiatric symptoms and cognitive decline, leading to premature death. The disease is caused by a mutation in the huntingtin gene, which codes for the huntingtin protein, and all individuals who inherit a pathogenic form of the mutant gene will eventually develop the condition. The huntingtin gene contains a series of repeats of the tri-nucleotide sequence CAG, which encodes for the amino acid glutamine. The number of repeats varies between individuals but if it exceeds 36, the huntingtin protein starts to form aggregates in the brain. Aggregation occurs when soluble protein precursors, known as oligomers, combine to form structures called fibrils, which in turn assemble into larger clusters. This phenomenon also occurs in several other tri-nucleotide diseases, each of which involves a mutated gene with an excess of tri-nucleotide repeats. Inside cells, proteins called chaperones regulate the folding of other proteins and help to prevent aggregate formation. A chaperone protein known as TRiC, which interacts with approximately 10% of proteins in the cytosol, has been shown to inhibit the aggregation of mutant huntingtin proteins. However, it has not been possible to map the structural interactions between TRiC and huntingtin to date. Now, Shahmoradian and Galaz-Montoya et al. have used cryo-electron tomography, combined with 3-D mapping and computer-aided reconstruction, to reveal the structure of a molecular complex consisting of TRiC and a pathogenic mutant huntingtin protein containing 51 CAG repeats. By imaging this system at different time points during the aggregation of mutant huntingtin, it was possible to characterize how the aggregates changed over time. They found that their shape differs in the presence and absence of TRiC, and that the chaperone interacts both with soluble huntingtin molecules—sequestering them so that they cannot join together—and with the tips of fibrils, preventing them from growing longer. By providing the first direct demonstration of how TRiC inhibits the aggregation of mutant huntingtin, the results of Shahmoradian and Galaz-Montoya et al. could aid in the design of TRiC-based drugs to be used in the treatment of Huntington’s disease.
Institutions: Baylor College of Medicine, Stanford University
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W2983230803