Interaction of Huntingtin and Apolipoprotein E with the endolysosomal system and autophagy
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Interaction of Huntingtin and Apolipoprotein E with the endolysosomal system and autophagy

  • Author(s): Fote, Gianna Marie
  • Advisor(s): Steffan, Joan S;
  • Thompson, Leslie M
  • et al.
No data is associated with this publication.
Creative Commons 'BY' version 4.0 license
Abstract

Loss of proteostasis and failure to effectively degrade cellular waste through the lysosome are common features among neurodegenerative diseases, including Alzheimer’s disease (AD) and Huntington’s disease (HD). Dysregulation of autophagy, the process of trafficking waste proteins to the lysosome for degradation, may lead to accumulation of toxic misfolded waste proteins and ultimately contribute to cell death. A single genetic mutation, a CAG repeat expansion within the HD gene, causes HD. Late-onset AD is sporadic and polygenic, but the APOE4 allele has emerged as the strongest genetic risk factor. Understanding what role wild-type HTT and APOE may play in autophagy pathways and how autophagy in turn contributes to clearance of these proteins may lead to a clearer understanding of disease pathogenesis and possibly opportunities for therapeutic intervention. This thesis describes my findings that APOE is degraded by autophagy, and that autophagic trafficking of APOE4 is increased in cellular models, causing lysosomal swelling and reduced overall autophagic flux. Knockout or knockdown of HTT modulates the contents of lysosomes, stimulating the lysosomal degradation of some autophagic substrates including APOE in hepatic cells. I investigated whether the combination of aberrant lysosomal trafficking of APOE4 with lysosomal trafficking induced by reduced HTT levels may cause toxicity in vivo. Preliminary studies of peripheral knockdown of HTT in APOE4-expressing mice have revealed toxicity in liver tissue, a major source of APOE expression. Ongoing and future studies of the interaction between these two neurodegenerative disease-associated proteins, and their function in and degradation by autophagy, may have implications for possible therapeutic strategies for HD involving peripheral total-HTT lowering, and for development of disease-modifying strategies for AD.

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This item is under embargo until June 29, 2023.