UC San Diego

Huntington’s disease is a heritable neurodegenerative disease caused by an autosomal dominant trinucleotide expansion of 35+ CAG repeats in the HTT gene while juvenile HD results from a trinucleotide expansion of 60+ CAG repeats. In both cases, an increased number of CAG repeats can increase the severity and onset of the disease. Additionally, there is a substantial dysregulation in protein interactions and cellular pathways in the putamen as well as global brain degeneration. Previous findings in proteomic analysis of expanded allele HTT knock-in mice have suggested mitochondrial toxicity and downregulated vesicle trafficking are some of the main causes of HD pathology, but this analysis has not been done with juvenile HD human brain tissue. To discover the dysregulated proteins in the cortex areas of Brodmann Area 4 and Brodmann Area 6 combined with the putamen, regions that regulate motor function, we performed mass spectrometry and proteomic analysis on trypsin-digested postmortem juvenile HD brain tissue and postmortem human control brain tissue to find dysregulated proteins in both conditions. Our findings showed: (1) proteins in juvenile HD only, (2) control only, (3) dysregulated proteins, (4) dysregulation of mitochondrial components in juvenile HD, (5) distinct neuropeptides in the juvenile HD and control proteome. The data suggest that mutant Htt causes gain and loss of expression of proteins in the human brain. In the cortex, the absence of mitochondrial pathway components indicates loss of function in this system. Furthermore, neuropeptides were found only in juvenile HD and control, shared, and dysregulated in juvenile HD.