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Scholarly Works (2 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2021)

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.

    Cover page: Juvenile Huntington’s Disease Human Brain Proteomics Analyses Reveals Dysregulated Mitochondrial Systems with Alterations in Neuropeptides
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2022)

    Background

    Huntington's disease (HD) is a genetic neurodegenerative disease caused by trinucleotide repeat (CAG) expansions in the human HTT gene encoding the huntingtin protein (Htt) with an expanded polyglutamine tract.

    Objective

    HD models from yeast to transgenic mice have investigated proteins interacting with mutant Htt that may initiate molecular pathways of cell death. There is a paucity of datasets of published Htt protein interactions that include the criteria of 1) defining fragments or full-length Htt forms, 2) indicating the number of poly-glutamines of the mutant and wild-type Htt forms, and 3) evaluating native Htt interaction complexes. This research evaluated such interactor data to gain understanding of Htt dysregulation of cellular pathways.

    Methods

    Htt interacting proteins were compiled from the literature that meet our criteria and were subjected to network analysis via clustering, gene ontology, and KEGG pathways using rigorous statistical methods.

    Results

    The compiled data of Htt interactors found that both mutant and wild-type Htt interact with more than 2,971 proteins. Application of a community detection algorithm to all known Htt interactors identified significant signal transduction, membrane trafficking, chromatin, and mitochondrial clusters, among others. Binomial analyses of a subset of reported protein interactor information determined that chromatin organization, signal transduction and endocytosis were diminished, while mitochondria, translation and membrane trafficking had enriched overall edge effects.

    Conclusion

    The data support the hypothesis that mutant Htt disrupts multiple cellular processes causing toxicity. This dataset is an open resource to aid researchers in formulating hypotheses of HD mechanisms of pathogenesis.
      Cover page: Mutant Huntingtin Protein Interaction Map Implicates Dysregulation of Multiple Cellular Pathways in Neurodegeneration of Huntington’s Disease
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