Quantitative Proteomic Analysis Reveals Similarities between Huntington’s Disease (HD) and Huntington’s Disease-Like 2 (HDL2) Human Brains

The
pathogenesis of HD and HDL2, similar progressive neurodegenerative
disorders caused by expansion mutations, remains incompletely understood.
No systematic quantitative proteomics studies, assessing global changes
in HD or HDL2 human brain, were reported. To address this deficit,
we used a stable isotope labeling-based approach to quantify the changes
in protein abundances in the cortex of 12 HD and 12 control cases
and, separately, of 6 HDL2 and 6 control cases. The quality of the
tissues was assessed to minimize variability due to post mortem autolysis.
We applied a robust median sweep algorithm to quantify protein abundance
and performed statistical inference using moderated test statistics.
1211 proteins showed statistically significant fold changes between
HD and control tissues; the differences in selected proteins were
verified by Western blotting. Differentially abundant proteins were
enriched in cellular pathways previously implicated in HD, including
Rho-mediated, actin cytoskeleton and integrin signaling, mitochondrial
dysfunction, endocytosis, axonal guidance, DNA/RNA processing, and
protein transport. The abundance of 717 proteins significantly differed
between control and HDL2 brain. Comparative analysis of the disease-associated
changes in the HD and HDL2 proteomes revealed that similar pathways
were altered, suggesting the commonality of pathogenesis between the
two disorders.