Biophysical Insights into How Lipid Membranes Modulate Huntingtin Aggregation Associated with Huntington's Disease

Abstract

The accumulation of nanoscale protein aggregates is a hallmark of many systemic and neurodegenerative disorders, including Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD). Disease-associated protein aggregation results in β-sheet-rich fibrils. However, a variety of globular protein aggregates, such as oligomers, are also associated with these diseases and may represent the most potent toxic species. Expansion of CAG triplet repeats encoding polyglutamine (polyQ) are responsible for at least ten disorders associated with polyQ induced protein aggregation. One of the aggregating proteins that has been extensively studied is exon1 of the huntingtin (htt) protein, which is directly implicated in HD and contains a prototype expanded polyQ domain. While mutant htt is detected predominantly in microscopic inclusion bodies in the cytoplasm and nucleus, it is also associated with many types of membranous organelles, including mitochondria, endoplasmic reticulum, tubulovesicles, endosomes, lysosomes and synaptic vesicles. Using a combination of ex situ and in situ AFM with other biochemical techniques, we are obtaining a detailed understanding of how htt interacts with lipid membranes with a focus in determining the role of polyQ length, flanking sequences adjacent to the polyQ domain, the lipid composition of the membrane, and how small molecules/peptides can interfere with this process. We are able to quantify the relative number of aggregate types formed as a function of time and also gain insight into their interactions with each other and surfaces along the aggregation pathway.