Most protein alterations related to Huntington’s occur early in life before disease symptoms show up, according to a group of scientists. They also suggest that early changes affect late-stage disease by irreversibly changing the biochemical activity in the mouse brain.
They also found a major variability in the types of changes seen during the course of the disease. The researchers thus argue against an HD model in which there is a gradual increase in the number and magnitude of protein changes and instead lean toward a more dynamic pathology.
The findings are reported in the April issue of Molecular and Cellular Proteomics in a paper titled "A Large Number of Protein Expression Changes Occur Early in Life and Precede Phenotype Onset in a Mouse Model for Huntington Disease (HD)."
Since HD is an inherited condition, changes likely occur earlier in development. To get a better sense of disease progression, the investigators used a large 2-D gel/mass spectrometry-based proteomics approach. They tracked HD-induced protein expression alterations and their kinetics in mice at two, four, six, eight, and 12 weeks of age. The researchers explain that the timeframe corresponds to absence of disease and early-, intermediate-, and late-stage HD.
The team observed 71–100% of HD stage-specific protein changes and drastic alterations in protein expression in almost 6% of the proteome occurred as early as two weeks. These changes included mainly the upregulation of proteins involved in glycolysis/gluconeogenesis and the downregulation of the actin cytoskeleton. An increase in glucose metabolism corresponds to the weight loss, which occurs early during HD progression.
These early-stage findings suggest a period of highly variable protein expression that precedes the onset of HD phenotypes. Although an up-regulation of glycolysis/gluconeogenesis-related protein alterations remained dominant during HD progression, late-stage alterations at 12 weeks showed an up-regulation of proteins involved in proteasomal function.
The early changes in HD, which coincide with a peak in protein alteration during normal mouse development, may be responsible for these massive later-stage changes, the scientists explain. Protein and mRNA data sets showed a large overlap on the level of affected pathways but not single proteins/mRNAs.
The researchers believe thus that HD is characterized by a highly dynamic disease pathology not represented by linear protein concentration alterations over the course of disease.
Past Findings in HD Research
Scientists Describe Molecular Process that Leads to Protein Clumps in Huntington's (Mar. 9, 2009)
New Cell Damage Clue Provided in Huntington’s Disease (Nov. 17, 2008)
Investigators Uncover Novel Mechanism in Huntington’s Disease (Jan. 9, 2008)
Researchers Found 234 Proteins that Interact with Huntington’s Molecule (May 11, 2007)
Molecules Discovered that Encourage Cells to Eat Huntington's Protein (May 8, 2007)